HETEROCYCLIC COMPOUNDS AS PI3K-y INHIBITORS

ABSTRACT

or pharmaceutically acceptable salts or stereoisomers thereof, which are inhibitors of PI3K-γ which are useful for the treatment of disorders such as autoimmune diseases, cancer, cardiovascular diseases, and neurodegenerative diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/165,390, filed Oct. 19, 2018, which is a divisional of U.S. patentapplication Ser. No. 15/631,417, filed Jun. 23, 2017, which claims thebenefit of U.S. Provisional Application No. 62/354,509, filed Jun. 24,2016, the disclosure of which is incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

The present invention provides heterocyclic compounds that modulate theactivity of phosphoinositide 3-kinases-gamma (PI3Kγ) and are useful inthe treatment of diseases related to the activity of PI3Kγ including,for example, autoimmune diseases, cancer, cardiovascular diseases, andneurodegenerative diseases.

BACKGROUND

The phosphoinositide 3-kinases (PI3Ks) belong to a large family of lipidsignaling kinases that phosphorylate phosphoinositides at the D3position of the inositol ring (Cantley, Science, 2002,296(5573):1655-7). PI3Ks are divided into three classes (class I, II,and III) according to their structure, regulation and substratespecificity. Class I PI3Ks, which include PI3Kα, PI3Kβ, PI3Kγ, andPI3Kδ, are a family of dual specificity lipid and protein kinases thatcatalyze the phosphorylation of phosphatidylinosito-4,5-bisphosphate(PIP₂) giving rise to phosphatidylinosito-3,4,5-trisphosphate (PIP₃).PIP₃ functions as a second messenger that controls a number of cellularprocesses, including growth, survival, adhesion and migration. All fourclass I PI3K isoforms exist as heterodimers composed of a catalyticsubunit (p110) and a tightly associated regulatory subunit that controlstheir expression, activation, and subcellular localization. PI3Kα,PI3Kβ, and PI3Kδ associate with a regulatory subunit known as p85 andare activated by growth factors and cytokines through a tyrosinekinase-dependent mechanism (Jimenez, et al., J Biol Chem., 2002,277(44):41556-62) whereas PI3Kγ associates with two regulatory subunits(p101 and p84) and its activation is driven by the activation ofG-protein-coupled receptors (Brock, et al., J Cell Biol., 2003,160(1):89-99). PI3Kα and PI3Kβ are ubiquitously expressed. In contrast,PI3Kγ and PI3Kδ are predominantly expressed in leukocytes(Vanhaesebroeck, et al., Trends Biochem Sci., 2005, 30(4):194-204).

Expression of PI3Kγ is mainly restricted to hematopoietic system,although it can be also detected at lower level in endothelium, heartand brain. PI3Kγ knock-out or kinase dead knock in mice are normal andfertile and do not present any overt adverse phenotypes. Analysis at thecellular level indicates that PI3Kγ is required for GPCR ligand-inducedPtdINs (3,4,5)P3 production, chemotaxis and respiratory burst inneutrophils. PI3Kγ-null macrophages and dendritic cell exhibit reducedmigration towards various chemoattractants. T-cells deficient in PI3Kγshow impaired cytokine production in response to anti-CD3 or Con Astimulation. PI3Kγ working downstream of adenosine A3A receptor iscritical for sustained degranulation of mast cells induced by FCεRIcross-linking with IgE. PI3Kγ is also essential for survival ofeosinophils (Ruckle et al., Nat. Rev. Drug Discovery, 2006, 5, 903-918)

Given its unique expression pattern and cellular functions, thepotential role of PI3Kγ in various autoimmune and inflammatory diseasemodels has been investigated with genetic and pharmacological tools. Inasthma and allergy models, PI3Kγ^(−/−) mice or mice treated with PI3Kγinhibitor showed a defective capacity to mount contact hypersensitivityand delayed-type hypersensitivity reactions. In these models, PI3Kγ wasshown to be important for recruitment of neutrophils and eosinopohils toairways and degranulation of mast cells (see e.g. Laffargue et al.,Immunity, 2002, 16, 441-451; Prete et al., The EMBO Journal, 2004, 23,3505-3515; Pinho et al., L. Leukocyte Biology, 2005, 77, 800-810; Thomaset al., Eur. J Immunol. 2005, 35, 1283-1291; Doukas et al., J Pharmacol.Exp Ther. 2009, 328, 758-765).

In two different acute pancreatitis models, genetic ablation of PI3Kγsignificantly reduced the extent of acinar cell injury/necrosis andneutrophil infiltration without any impact on secretive function ofisolated pancreatic acini (Lupia et al., Am. J Pathology, 2004, 165,2003-2011). PI3Kγ^(−/−) mice were largely protected in four differentmodels of rheumatoid arthritis (CIA, α-CII-IA, K/BxN serum transfer andTNF transgenic) and PI3Kγ inhibition suppressed the progression of jointinflammation and damage in the CIA and α-CII-IA models (see e.g., Campset al., Nat. Medicine, 2005, 11, 939-943; Randis et al., Eur. J Immunol,2008, 38, 1215-1224; Hayer et al., FASB J., 2009, 4288-4298). In theMRL-lpr mouse model of human systemic lupus erythematous, inhibition ofPI3Kγ reduced glomerulonephritis and prolonged life span (Barber et al.,Nat. Medicine, 2005, 9, 933-935).

There is evidence suggesting that chronic inflammation due toinfiltration by myeloid-derived cells is a key component in theprogression of neurodegeneration diseases, such as Alzheimer's disease(AD) (Giri et al., Am. J. Physiol. Cell Physiol., 2005, 289, C264-C276;El Khoury et al., Nat. Med., 2007, 13, 432-438). In line with thissuggestion, PI3Kγ inhibition was shown to attenuate Aβ(1-40)-inducedaccumulation of activated astrocytes and microglia in the hippocampusand prevent the peptide-induced congnitive deficits and synapticdysfunction in a mouse model of AD (Passos et al., Brain Behav. Immun.2010, 24, 493-501). PI3Kγ deficiency or inhibition also was shown todelay onset and alleviate symptoms in experimental autoimmuneencephalomyelitis in mice, a mouse model of human multiple sclerosis,which is another form of neurodegeneration disease (see e.g., Rodrigueset al., J. Neuroimmunol. 2010, 222, 90-94; Berod et al., Euro. JImmunol. 2011, 41, 833-844; Comerford et al., PLOS one, 2012, 7, e45095;Li et al., Neuroscience, 2013, 253, 89-99).

Chronic inflammation has been formally recognized as one of thehallmarks for many different types of cancers. Accordingly, selectiveanti-inflammatory drugs represent a novel class of anti-cancer therapies(Hanahan and Weinberg, Cell, 2011, 144, 646-674). Since PI3Kγ isreported to mediate various inflammatory processes, its role as animmune oncology target has also been investigated. A recent studyreported that PI3Kγ deficiency suppressed tumor growth in the syngeneicmodels of lung cancer, pancreatic cancer and melanoma (LLC, PAN02 andB16). PI3Kγ deficiency or inhibition also inhibited tumor growth in aspontaneous breast cancer model (Schmid et al., Cancer Cell, 2011, 19,715-727). A further study reported that PI3Kγ deficiency couldameliorate inflammation and tumor growth in mice havingcolitis-associated colon cancer, (Gonzalez-Garcia et al.,Gastroenterology, 2010, 138, 1373-1384). Detailed mechanistic analysisindicates that tumor infiltration by CD11b⁺ myeloid cells can causeprotumorigenic inflammation at tumor sites and PI3Kγ in the myeloidcells is critical in mediating signaling of various chemoattractants inbring the cells to the tumor (Schmid et al., Cancer Cell, 2011, 19,715-727). Other studies suggest that PI3Kγ is also required fordifferentiation of naïve myeloid cells into M2 macrophages at tumorsites. M2 macrophages promote tumor growth and progression by secretingimmunosuppressive factors such arginase 1, which depletes the tumormicroenvironment of arginine, thereby promoting T-cell death and NK cellinhibition (Schmidt et al., Cancer Res. 2012, 72 (Suppl 1: Abstract,411; Kaneda et al., Cancer Res., 74 (Suppl 19: Abstact 3650)).

In addition to its potential role in promoting protumorigenicmicroenvironment, PI3Kγ may play a direct role in cancer cells. PI3Kγ isreported to be required for signaling from the Kaposi'ssarcoma-associated herpevirus encoded vGPCR oncogene and tumor growth ina mouse model of sarcoma (Martin et al., Cancer Cell, 2011, 19,805-813). PI3Kγ was also suggested to be required for growth of T-ALL(Subramanjam et al., Cancer Cell, 2012, 21, 459-472), PDAC and HCC cells(Falasca and Maffucci, Frontiers in Physiology, 2014, 5, 1-10).Moreover, in a survey of driver mutations in pancreatic cancer, PI3Kγgene was found to contain second highest scoring predicted drivenmutation (R839C) among the set of genes not previously identified as adriver in pancreatic cancer (Carter et al., Cancer Biol. Ther. 2010, 10,582-587).

Finally, PI3Kγ deficiency also has been reported to offer protection toexperimental animals in different cardiovascular disease models. Forexamples, lack of PI3Kγ would reduce angiotension-evoked smooth musclecontraction and, therefore, protect mice from angiotension-inducedhypertension (Vecchione et al., J. Exp. Med. 2005, 201, 1217-1228). Inrigorous animal myocardial infarction models, PI3Kγ inhibition providedpotent cardioprotection, reducing infarct development and preservingmyocardial function (Doukas et al., Proc. Natl. Acad. Sci. USA, 2006,103, 19866-19871).

For these reasons, there is a need to develop new PI3Kγ inhibitors thatcan be used for the treatment of diseases such as cancer, autoimmunedisorders, and inflammatory and cardiac diseases. This application isdirected to this need and others.

SUMMARY

The present invention related to, inter alia, compounds of Formula (I):

or pharmaceutically acceptable salts, wherein constituent members aredefined herein.

The present invention further provides pharmaceutical compositionscomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

The present invention further provides pharmaceutically acceptable saltforms of the compounds of Formula (I).

The present invention further provides crystalline forms of thecompounds of Formula (I).

The present invention further provides methods of inhibiting an activityof PI3Kγ kinase comprising contacting the kinase with a compound ofFormula (I), or a pharmaceutically acceptable salt thereof.

The present invention further provides methods of treating a disease ora disorder associated with abnormal PI3Kγ kinase expression or activityin a patient by administering to a patient a therapeutically effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof.

The present invention further provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

The present invention further provides use of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, for the preparation of amedicament for use in any of the methods described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an X-Ray Powder Diffraction (XRPD) pattern characteristicof the crystalline compound of Example 253.

FIG. 2 shows a Differential Scanning Calorimetry (DSC) thermogramcharacteristic of the crystalline compound of Example 253.

FIG. 3 shows a TGA thermogram characteristic of the crystalline compoundof Example 253.

FIG. 4 shows an X-Ray Powder Diffraction (XRPD) pattern characteristicof the crystalline hydrochloric acid salt of Example 254.

FIG. 5 shows a Differential Scanning Calorimetry (DSC) thermogramcharacteristic of the crystalline hydrochloric acid salt of Example 254.

FIG. 6 shows a TGA thermogram characteristic of the crystallinehydrochloric acid salt of Example 254.

FIG. 7 shows an X-Ray Powder Diffraction (XRPD) pattern characteristicof the crystalline benzenesulfonic acid salt of Example 255.

FIG. 8 shows a Differential Scanning Calorimetry (DSC) thermogramcharacteristic of the crystalline benzenesulfonic acid salt of Example255.

FIG. 9 shows a TGA thermogram characteristic of the crystallinebenzenesulfonic acid salt of Example 255.

DETAILED DESCRIPTION Compounds

The present application provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein:

X¹ is N or CR¹;

X² is N or CR²;

X³ is N or CR³;

X⁴ is N or CR⁴;

X⁵ is N or CR⁵;

X⁶ is N or CR⁶;

X³, X⁴, X⁵ and X⁶ are not simultaneously N;

R⁷ is H or C₁₋₆alkyl optionally substituted with 1, 2 or 3 groupsindependently selected from halo, OH, oxo, CN, C₃₋₆cycloalkyl, 4-6membered heterocycloalkyl, C₆₋₁₀aryl, C₁₋₆ haloalkyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, NH₂, C₁₋₆alkyl-NH— and (C₁₋₆alkyl)₂N—;

R¹, R², R³, R⁴, R⁵, R⁶ and R⁸ are each independently selected from H, D,halo, oxo, C₁₋₆ alkyl, C₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-14 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 memberedheteroaryl)-C₁₋₄alkyl-, (4-14 membered heterocycloalkyl)-C₁₋₄alkyl-, CN,NO₂, OR^(a1), SR^(a1), NHOR^(a1), C(O)R^(a1), C(O)NR^(a1)R^(a1),C(O)OR^(a1), OC(O)R^(a1), OC(O)NR^(a1)R^(a1), NHR^(a1), NR^(a1)R^(a1),NR^(a1)C(O)R^(a1), NR^(a1)C(O)OR^(a1), NR^(a1)C(O)NR^(a1)R^(a1),C(═NR^(a1))R^(a1), C(═NR^(a1))NR^(a1)R^(a1),NR^(a1)C(═NR^(a1))NR^(a1)R^(a1), NR^(a1)C(═NOH)NR^(a1)R^(a1),NR^(a1)C(═NCN)NR^(a1)R^(a1), NR^(a1)S(O)R^(a1), NR^(a1)S(O)₂R^(a1),NR^(a1)S(O)₂NR^(a1)R^(a1), S(O)R^(a1), S(O)NR^(a1)R^(a1), S(O)₂R^(a1),SF₅, —P(O)R^(a1)R^(a1), —P(O)(OR^(a1))(OR^(a1)), B(OR^(a1))₂ andS(O)₂NR^(a1)R^(a1), wherein the C₁₋₆alkyl, C₁₋₆alkoxy, C₂₋₆alkenyl,C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-14membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-14 membered heterocycloalkyl)-C₁₋₄alkyl- of R¹, R², R³, R⁴, R⁵, R⁶and R⁸ are each optionally substituted with 1, 2, 3, 4 or 5independently selected R^(b) substituents;

R⁹ is H, D, CN, C(O), NH₂, —OH, —COOH, —NH(C₁₋₆alkyl), —NH(C₁₋₆alkyl)₂,C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy or C₁₋₆haloalkoxy, wherein theC₁₋₆alkyl is optionally substituted with 1, 2 or 3 independentlyselected R^(q) substituents;

R¹⁰ is selected from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl,5-10 membered heteroaryl, 4-14 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 memberedheteroaryl)-C₁₋₄alkyl-, (4-14 membered heterocycloalkyl)-C₁₋₄alkyl-,OR^(a2), SR^(a2), NHOR^(a2), C(O)R^(a2), C(O)NR^(a2)R^(a2), C(O)OR^(a2),NHR^(a2), NR^(a2)R^(a2), NR^(a2)C(O)R^(a2), NR^(a2)C(O)OR^(a2),NR^(a2)C(O)NR^(a2)R^(a2), C(═NR^(a2))R^(a2), C(═NR^(a2))NR^(a2)R^(a2),NR^(a2)C(═NR^(a2))NR^(a2)R^(a2), NR^(a2)S(O)R^(a2), NR^(a2)S(O)₂R^(a2),NR^(a2)S(O)₂NR^(a2)R^(a2), S(O)R^(a2), S(O)NR^(a2)R^(a2), S(O)₂R^(a2),S(O)₂NR^(a2)R^(a2), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-14membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-14 membered heterocycloalkyl)-C₁₋₄alkyl- of R¹⁰ are each optionallysubstituted with 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R^(b)substituents;

L is

wherein each R¹¹ is independently H, C₁₋₆alkyl, or C₃₋₁₀cycloalkyloptionally substituted with 1 or 2 R^(q) substituents and wherein thesingle wavy line indicates the point of attachment to R¹⁰ and the doublewavy line indicates the point of attachment to the 6-membered ring A;

or when L is

R¹⁰ and R¹¹ optionally taken together with the nitrogen atom to whichthey are attached, form a 4 to 14 membered heterocycloalkyl or a 4 to 14membered heterocycloalkyl-C₁₋₄alkyl- having 0 to 4 additionalheteroatoms as a ring member, each of which is independently selectedfrom N, O and S, wherein the 4 to 14-membered heterocycloalkyl formed byR¹⁰, R¹¹ and N is optionally substituted with 1, 2, 3, 4, 5, 6, 7 or 8independently selected R^(b) substituents;

R^(a1) and R^(a2) are each independently selected from H, D, C₁₋₆alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl,5-10 membered heteroaryl, 4-14 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 memberedheteroaryl)-C₁₋₄alkyl-, and (4-14 membered heterocycloalkyl)-C₁₋₄alkyl-,wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-14 memberedheterocycloalkyl)-C₁₋₄alkyl- of R^(a1) and R^(a2) are each optionallysubstituted with 1, 2, 3, 4, or 5 independently selected R^(d)substituents;

each R^(b) substituent is independently selected from D, halo, oxo,C₁₋₄alkyl, CM alkoxy, CM haloalkyl, C₁₋₄haloalkoxy, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl. 5-10 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NOH)NR^(c)R^(c), NR^(c)C(═NCN)NR^(c)R^(c), SF₅,—P(O)R^(c)R^(c), —P(O)(OR^(c))(OR^(c)), NHR^(c), NR^(c)R^(c),NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c),NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c),S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl,CM alkoxy, C₁₋₄haloalkyl, C₁₋₄haloalkoxy, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl.5-10 membered heteroaryl, 4-14 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 memberedheteroaryl)-C₁₋₄alkyl- and (4-14 membered heterocycloalkyl)-C₁₋₄alkyl-of R^(b) are each further optionally substituted with 1, 2, or 3independently selected R^(d) substituents;

each R^(c) is independently selected from H, D, C₁₋₆alkyl,C₁₋₄haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl.5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 memberedheteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-,wherein the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- of R^(c) are each optionally substitutedwith 1, 2, 3, 4, or 5 independently selected R^(f) substituents;

each R^(f) is independently selected from C₁₋₄alkyl, C₁₋₄haloalkyl,C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, halo, CN, NHOR^(g), OR^(g),SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NOH)NR^(g)R^(g),NR^(g)C(═NCN)NR^(g)R^(g), SF₅, —P(O)R^(g)R^(g), —P(O)(O^(g))(OR^(g)),S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g),NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); wherein the C₁₋₄alkyl,C₁₋₄haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 memberedheteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-of R^(f) are each optionally substituted with 1, 2, 3, 4, or 5independently selected R^(n) substituents;

each R^(n) is independently selected from C₁₋₄alkyl, C₁₋₄haloalkyl,halo, CN, R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o),C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o),NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o),NR^(o)C(═NOH)NR^(o)R^(o), NR^(o)C(═NCN)NR^(o)R^(o), SF₅,—P(O)R^(o)R^(o), —P(O)(OR^(o))(OR^(o)), S(O)R^(o), S(O)NR^(o)R^(o),S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), andS(O)₂NR^(o)R^(o);

each R^(d) is independently selected from D, oxo, C₁₋₆alkyl,C₁₋₆haloalkyl, halo, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, CN, NH₂, NHOR^(e), OR^(e),SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e),OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NOH)NR^(e)R^(e),NR^(e)C(═NCN)NR^(e)R^(e), SF₅, —P(O)R^(e)R^(e), —P(O)(OR^(e))(OR^(e)),S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e),NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e), wherein the C₁₋₆alkyl,C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- of R^(d) are each optionally substitutedwith 1, 2, or 3 independently selected R^(f) substituents;

each R^(e) is independently selected from H, D, CN, C₁₋₆alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 memberedheteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-,wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- of R^(e) are each optionally substitutedwith 1, 2 or 3 independently selected R^(g) substituents;

each R^(g) is independently selected from H, D, C₁₋₆alkyl,C₁₋₄haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 memberedheteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-,wherein the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- of R^(g) are each optionally substitutedwith 1, 2 or 3 independently selected R^(p) substituents;

each R^(p) is independently selected from C₁₋₄alkyl, C₁₋₄haloalkyl,C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, halo, CN, NHOR^(r), OR^(r),SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r),OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), SF₅, —P(O)R^(r)R^(r), —P(O)(OR^(r))(OR^(r)),S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r),NR^(r)S(O)₂NR^(r)R^(r), and S(O)₂NR^(r)R^(r); or any two R^(a1)substituents together with the nitrogen atom to which they are attachedform a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl groupoptionally substituted with 1, 2 or 3 independently selected R^(h)substituents;

each R^(h) is independently selected from C₁₋₆alkyl, C₃₋₁₀cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄alkyl-, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, halo, CN, OR^(i), SR^(i), NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i),C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i),NR^(i)C(O)R^(i), NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i),C(═NR^(i))NR^(i)R^(i), NR^(i)C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NOH)NR^(i)R^(i), NR^(i)C(═NCN)NR^(i)R^(i), SF₅,—P(O)R^(i)R^(i), —P(O)(OR^(i))(OR^(i)), S(O)R^(i), S(O)NR^(i)R^(i),S(O)₂R^(i), NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), andS(O)₂NR^(i)R^(i), wherein the C₁₋₆alkyl, C₃₋₁₀cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄alkyl- of R^(h) are each furtheroptionally substituted by 1, 2, or 3 independently selected R^(j)substituents;

each R^(j) is independently selected from C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5or 6-membered heteroaryl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halo, C₁₋₄alkyl,C₁₋₄haloalkyl, CN, NHOR^(k), OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k),C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k),NR^(k)C(O)R^(k), NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k),C(═NR^(k))NR^(k)R^(k), NR^(k)C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NOH)NR^(k)R^(k), NR^(k)C(═NCN)NR^(k)R^(k), SF₅,—P(O)R^(k)R^(k), —P(O)(OR^(k))(OR^(k)), S(O)R^(k), S(O)NR^(k)R^(k),S(O)₂R^(k), NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), andS(O)₂NR^(k)R^(k); or two R^(j) groups attached to the same carbon atomof the 4- to 10-membered heterocycloalkyl taken together with the carbonatom to which they attach form a C₃₋₆cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

or any two R^(a2) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3 R^(h)substituents;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(r) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

each R^(i), R^(k), R^(o) or R^(r) is independently selected from H, D,C₁₋₄alkyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl,C₁₋₄haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl,C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5 or 6-membered heteroaryl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl of R^(i), R^(k), R^(o) or R^(r) are each optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents;

each R^(q) is independently selected from D, OH, CN, —COOH, NH₂, halo,C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₄alkylthio,phenyl, 5-6 membered heteroaryl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, —CONHR¹², —NHC(O)R¹², —OC(O)R¹², —C(O)OR¹², —C(O)R¹²,—SO₂R¹², —NHSO₂R¹², —SO₂NHR¹² and NR¹²R¹², wherein the C₁₋₆alkyl,phenyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl ofR^(q) are each optionally substituted with OH, CN, —COOH, NH₂,C₁₋₆alkoxy, C₃₋₆cycloalkyl or 4-6 membered heterocycloalkyl;

and each R¹² is independently C₁₋₆alkyl;

provided that:

when R⁷ is C₁₋₆alkyl, R¹⁰-L- is other than cyclopropylsulfamoyl andmethanesulfonamido;

when R⁷ is cyclopropylmethyl, R¹⁰-L- is other than methanesulfonamido;

when R⁷ is 2-(4-morpholino)ethyl, R¹⁰-L- is other than methanesulfonyl;and

the compound is other than3-(8-aminoimidazo[1,2-a]pyridin-3-yl)-2-(1H-tetrazol-5-yl)benzenesulfonamide.

In some embodiments:

X¹ is N or CR¹;

X² is N or CR²;

X³ is N or CR³;

X⁴ is N or CR⁴;

X⁵ is N or CR⁵;

X⁶ is N or CR⁶;

X³, X⁴, X⁵ and X⁶ are not simultaneously N;

R⁷ is H or C₁₋₆alkyl optionally substituted with 1, 2 or 3 groupsindependently selected from halo, OH, oxo, CN, C₃₋₆cycloalkyl, 4-6membered heterocycloalkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy,NH₂, C₁₋₆alkyl-NH— and (C₁₋₆alkyl)₂N—;

R¹, R², R³, R⁴, R⁵, R⁶ and R⁸ are each independently selected from H,halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆haloalkoxy, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄alkyl-, CN, NO₂, OR^(a1), SR^(a1),NHOR^(a1), C(O)R^(a1), C(O)NR^(a1)R^(a1), C(O)OR^(a1), OC(O)R^(a1),OC(O)NR^(a1)R^(a1), NHR^(a1), NR^(a1)R^(a1), NR^(a1)C(O)R^(a1),NR^(a1)C(O)OR^(a1), NR^(a1)C(O)NR^(a1)R^(a1), C(═NR^(a1))R^(a1mi),C(═NR^(a1))NR^(a1)R^(a1), NR^(a1)C(═NR^(a1))NR^(a1)R^(a1),NR^(a1)C(═NOH)NR^(a1)R^(a1), NR^(a1)C(═NCN)NR^(a1)R^(a1),NR^(a1)S(O)R^(a1), NR^(a1)S(O)₂R^(a1), NR^(a1)S(O)₂NR^(a1)R^(a1),S(O)R^(a1), S(O)NR^(a1)R^(a1), S(O)₂R^(a1), SF₅, —P(O)R^(a1)R^(a1),—P(O)(OR^(a1))(OR^(a1)) and S(O)₂NR^(a1)R^(a1), wherein the C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- of R¹, R², R³, R⁴, R⁵, R⁶and R⁸ are each optionally substituted with 1, 2, 3, 4 or 5independently selected R^(b) substituents;

R⁹ is H, CN, NH₂, —OH, —COOH, —NH(C₁₋₆alkyl), —NH(C₁₋₆alkyl)₂,C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy or C₁₋₆haloalkoxy, wherein theC₁₋₆alkyl is optionally substituted with 1, 2 or 3 independentlyselected R^(q) substituents;

R¹⁰ is selected from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 memberedheteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-,OR^(a2), SR^(a2), NHOR^(a2), C(O)R^(a2), C(O)NR^(a2)R^(a2), C(O)OR^(a2),NHR^(a2), NR^(a2)R^(a2), NR^(a2)C(O)R^(a2), NR^(a2)C(O)OR^(a2),NR^(a2)C(O)NR^(a2)R^(a2), C(═NR^(a2))R^(a2), C(═NR^(a2))NR^(a2)R^(a2),NR^(a2)C(═NR^(a2))NR^(a2)R^(a2), NR^(a2)S(O)R^(a2), NR^(a2)S(O)₂R^(a2),NR^(a2)S(O)₂NR^(a2)R^(a2), S(O)R^(a2), S(O)NR^(a2)R^(a2), S(O)₂R^(a2),and S(O)₂NR^(a2)R^(a2), wherein the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- of R¹⁰ are each optionally substituted with1, 2, 3, 4 or 5 independently selected R^(b) substituents;

L is

wherein each R¹¹ is independently H or C₁₋₆alkyl optionally substitutedwith 1 or 2 R^(q) substituents and wherein the single wavy lineindicates the point of attachment to R¹⁰ and the double wavy lineindicates the point of attachment to the 6-membered ring A;

or when L is

R¹⁰ and R¹¹ optionally taken together with the nitrogen atom to whichthey are attached, form 4-, 5-, 6- or 7-membered heterocycloalkyl having0 to 1 additional heteroatom as a ring member selected from N, O and S,wherein the 4-, 5-, 6- or 7-membered heterocycloalkyl formed by R¹⁰, R¹¹and N is optionally substituted with 1, 2 or 3 independently selectedR^(q) substituents;

or two substituents attached to the same ring carbon atom of theheterocycloalkyl formed by R¹⁰ and R¹¹, taken together with the carbonatom to which they are attached form C₃₋₆ cycloalkyl, optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents;

R^(a1) and R^(a2) are each independently selected from H, C₁₋₆alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 memberedheteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-,wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- of R^(a1) and R^(a2) are each optionallysubstituted with 1, 2, 3, 4, or 5 independently selected R^(d)substituents;

each R^(b) substituent is independently selected from halo, C₁₋₄alkyl,C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 memberedheteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, CN,OH, NH₂, NO₂, NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c),C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NOH)NR^(c)R^(c),NR^(c)C(═NCN)NR^(c)R^(c), SF₅, —P(O)R^(c)R^(c), —P(O)(OR^(c))(OR^(c)),NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) orS(O)₂NR^(c)R^(c); wherein the C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- of R^(b) are each further optionallysubstituted with 1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆alkyl, C₁₋₄haloalkyl,C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- of R^(c) are each optionallysubstituted with 1, 2, 3, 4, or 5 independently selected R^(f)substituents;

each R^(f) is independently selected from C₁₋₄alkyl, C₁₋₄haloalkyl,C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, halo, CN, NHOR^(g), OR^(g),SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NOH)NR^(g)R^(g),NR^(g)C(═NCN)NR^(g)R^(g). SF₅, —P(O)R^(g)R^(g), —P(O)(OR^(g))(OR^(g)),S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g),NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); wherein the C₁₋₄alkyl,C₁₋₄haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 memberedheteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-of R^(f) are each optionally substituted with 1, 2, 3, 4, or 5independently selected R^(n) substituents;

each R^(n) is independently selected from C₁₋₄alkyl, C₁₋₄haloalkyl,halo, CN, R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o),C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o),NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o),NR^(o)C(═NOH)NR^(o)R^(o), NR^(o)C(═NCN)NR^(o)R^(o), SF₅,—P(O)R^(o)R^(o), —P(O)(OR^(o))(OR^(o)), S(O)R^(o), S(O)NR^(o)R^(o),S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), andS(O)₂NR^(o)R^(o);

each R^(d) is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,halo, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10membered heterocycloalkyl)-C₁₋₄alkyl-, CN, NH₂, NHOR^(e), OR^(e),SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e),OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NOH)NR^(e)R^(e),NR^(e)C(═NCN)NR^(e)R^(e), SF₅, —P(O)R^(e)R^(e), —P(O)(OR^(e))(OR^(e)),S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e),NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e), wherein the C₁₋₆alkyl,C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- of R^(d) are each optionally substitutedwith 1, 2, or 3 independently selected R^(f) substituents;

each R^(e) is independently selected from H, CN, C₁₋₆alkyl,C₁₋₄haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 memberedheteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-,wherein the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- of R^(e) are each optionally substitutedwith 1, 2 or 3 independently selected R^(g) substituents;

each R^(g) is independently selected from H, C₁₋₆alkyl, C₁₋₄haloalkyl,C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- of R^(g) are each optionallysubstituted with 1, 2 or 3 independently selected R^(p) substituents;

each R^(p) is independently selected from C₁₋₄alkyl, C₁₋₄haloalkyl,C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, halo, CN, NHOR^(r), OR^(r),SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r),OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), SF₅, —P(O)R^(r)R^(r), —P(O)(OR^(r))(OR^(r)),S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r),NR^(r)S(O)₂NR^(r)R^(r), and S(O)₂NR^(r)R^(r); or any two R^(a1)substituents together with the nitrogen atom to which they are attachedform a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl groupoptionally substituted with 1, 2 or 3 independently selected R^(h)substituents;

each R^(h) is independently selected from C₁₋₆alkyl, C₃₋₁₀cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄alkyl-, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, halo, CN, OR^(i), SR^(i), NHOR^(i), C(O)R^(i). C(O)NR^(i)R^(i),C(O)OR^(i). OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i),NR^(i)C(O)R^(i), NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i),C(═NR^(i))NR^(i)R^(i), NR^(i)C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NOH)NR^(i)R^(i), NR^(i)C(═NCN)NR^(i)R^(i), SF₅,—P(O)R^(i)R^(i), —P(O)(OR^(i))(OR^(i)), S(O)R^(i). S(O)NR^(i)R^(i),S(O)₂R^(i), NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), andS(O)₂NR^(i)R^(i), wherein the C₁₋₆alkyl, C₃₋₁₀cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄alkyl- of R^(h) are each furtheroptionally substituted by 1, 2, or 3 independently selected R^(j)substituents;

each R^(j) is independently selected from C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5or 6-membered heteroaryl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halo, C₁₋₄alkyl,C₁₋₄haloalkyl, CN, NHOR^(k), OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k),C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k),NR^(k)C(O)R^(k), NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k),C(═NR^(k))NR^(k)R^(k), NR^(k)C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NOH)NR^(k)R^(k), NR^(k)C(═NCN)NR^(k)R^(k), SF₅,—P(O)R^(k)R^(k), —P(O)(OR^(k))(OR^(k)), S(O)R^(k), S(O)NR^(k)R^(k),S(O)₂R^(k), NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), andS(O)₂NR^(k)R^(k); or two R^(h) groups attached to the same carbon atomof the 4- to 10-membered heterocycloalkyl taken together with the carbonatom to which they attach form a C₃₋₆cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

or any two R^(a2) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3 R^(h)substituents;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(r) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

each R^(i), R^(k), R^(o) or R^(r) is independently selected from H,C₁₋₄alkyl, C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5 or 6-membered heteroaryl,C₁₋₄haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl,C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5 or 6-membered heteroaryl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl of R^(i), R^(k), R^(o) or R^(r) are each optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents;

each R^(q) is independently selected from OH, CN, —COOH, NH₂, halo,C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₄alkylthio,phenyl, 5-6 membered heteroaryl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, —CONHR¹², —NHC(O)R¹², —OC(O)R¹², —C(O)OR¹², —C(O)R¹²,—SO₂R¹², —NHSO₂R¹², —SO₂NHR¹² and NR¹²R¹², wherein the C₁₋₆alkyl,phenyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl ofR^(q) are each optionally substituted with OH, CN, —COOH, NH₂,C₁₋₆alkoxy, C₃₋₆cycloalkyl or 4-6 membered heterocycloalkyl; and

each R¹² is independently C₁₋₆alkyl;

provided that:

when R⁷ is C₁₋₆alkyl, R¹⁰-L- is other than cyclopropylsulfamoyl andmethanesulfonamido;

when R⁷ is cyclopropylmethyl, R¹⁰-L- is other than methanesulfonamido;

when R⁷ is 2-(4-morpholino)ethyl, R¹⁰-L- is other than methanesulfonyl;and

the compound is other than3-(8-aminoimidazo[1,2-a]pyridin-3-yl)-2-(1H-tetrazol-5-yl)benzenesulfonamide.

In some embodiments of the previous embodiment, each R^(b) isindependently selected from R^(q).

In some embodiments:

X¹ is N or CR¹;

X² is N or CR²;

X³ is N or CR³;

X⁴ is N or CR⁴;

X⁵ is N or CR⁵;

X⁶ is N or CR⁶;

X³, X⁴, X⁵ and X⁶ are not simultaneously N;

R⁷ is H, methyl, or ethyl, wherein said methyl and ethyl are eachoptionally substituted with 1, 2 or 3 groups independently selected fromhalo, OH, oxo, CN, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, NH₂,C₁₋₆alkyl-NH—, and (C₁₋₆alkyl)₂N—;

R¹, R², R⁴, R⁵, R⁶ and R⁸ are each independently selected from H, halo,C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy,C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, CN, NO₂, OR^(a1), C(O)R^(a1),C(O)NR^(a1)R^(a1), C(O)OR^(a1), OC(O)R^(a1), OC(O)NR^(a1)R^(a1),NR^(a1)R^(a1), NR^(a1)C(O)R^(a1), NR^(a1)C(O)OR^(a1),NR^(a1)C(O)NR^(a1)R^(a1), NR^(a1)S(O)R^(a1), NR^(a1)S(O)₂R^(a1),NR^(a1)S(O)₂NR^(a1)R^(a1), S(O)R^(a1), S(O)NR^(a1)R^(a1), S(O)₂R^(a1),and S(O)₂NR^(a1)R^(a1), wherein the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- of R¹, R², R³, R⁴, R⁵, R⁶ and R⁸ are eachoptionally substituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

R³ is H, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, OH,CN, NH₂, C₁₋₆ alkyl-NH—, or (C₁₋₆alkyl)₂N—;

R⁹ is H, CN, NH₂, —OH, —COOH, —NH(C₁₋₆alkyl), —NH(C₁₋₆alkyl)₂,C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy or C₁₋₆haloalkoxy, wherein theC₁₋₆alkyl is optionally substituted with 1, 2 or 3 independentlyselected R^(q) substituents;

R¹⁰ is selected from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆haloalkoxy, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄alkyl-, OR^(a2), C(O)R^(a2),C(O)NR^(a2)R^(a2), C(O)OR^(a2), NR^(a2)R^(a2), NR^(a2)C(O)R^(a2),NR^(a2)C(O)OR^(a2), NR^(a2)C(O)NR^(a2)R^(a2), NR^(a2)S(O)R^(a2),NR^(a2)S(O)₂R^(a2), NR^(a2)S(O)₂NR^(a2)R^(a2), S(O)R^(a2), S(O)₂R^(a2),wherein the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- of R¹⁰ are each optionally substituted with1, 2, 3, 4 or 5 independently selected R^(b) substituents;

L is

wherein each R¹¹ is independently H or C₁₋₆alkyl optionally substitutedwith 1 or 2 R^(q) substituents and wherein the single wavy lineindicates the point of attachment to R¹⁰ and the double wavy lineindicates the point of attachment to the 6-membered ring A;or when L is

R¹⁰ and R¹¹ optionally taken together with the nitrogen atom to whichthey are attached, form 4-, 5-, 6-, 7-, 8-, 9-, or 10-memberedheterocycloalkyl having 0 to 1 additional heteroatom as a ring memberselected from N, O and S, wherein the form 4-, 5-, 6-, 7-, 8-, 9-, or10-membered heterocycloalkyl formed by R¹⁰, R¹¹ and N is optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents;

R^(a1) and R^(a2) are each independently selected from H, C₁₋₆alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 memberedheteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-,wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- of R^(a1) and R^(a2) are each optionallysubstituted with 1, 2, 3, 4, or 5 independently selected R^(d)substituents;

each R^(b) substituent is independently selected from halo, C₁₋₄alkyl,C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 memberedheteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, CN,NO₂, OR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) orS(O)₂NR^(c)R^(c); wherein the C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄haloalkoxy,C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- of R^(b) are each further optionallysubstituted with 1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆alkyl, C₁₋₄haloalkyl,C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl-;

each R^(d) is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,halo, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10membered heterocycloalkyl)-C₁₋₄alkyl-, CN, OR^(e), C(O)R^(e),C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NR^(e)R^(e),NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e);

each R^(e) is independently selected from H, CN, C₁₋₆alkyl,C₁₋₄haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 memberedheteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-;

or any two R^(a1) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3independently selected R^(h) substituents;

or any two R^(a2) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3independently selected R^(h) substituents;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

each R^(h) is independently selected from C₁₋₆alkyl, C₃₋₁₀cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄alkyl-, C₁₋₆haloalkyl, C₂₋₆ alkenyl,C₂₋₆alkynyl, halo, CN, OR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i).OC(O)R^(i), OC(O)NR^(i)R^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), S(O)R^(i), S(O)NR^(i)R^(i),S(O)₂R^(i), NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), andS(O)₂NR^(i)R^(i)

-   -   each R^(i) is independently selected from H, C₁₋₄alkyl,        C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5 or 6-membered heteroaryl,        C₁₋₄haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

each R^(q) is independently selected from OH, CN, —COOH, NH₂, halo,C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₄alkylthio,phenyl, 5-6 membered heteroaryl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, —CONHR¹², —NHC(O)R¹², —OC(O)R¹², —C(O)OR¹², —C(O)R¹²,—SO₂R¹², —NHSO₂R¹², —SO₂NHR¹² and NR¹²R¹²; and

each R¹² is independently C₁₋₆alkyl.

In some embodiments of the previous embodiment, one or more hydrogenatoms can be replaced by deuterium atoms (e.g., one or more hydrogenatoms of a C₁₋₆alkyl group can be replaced by deuterium atoms).

In some embodiments:

X¹ is N or CR¹;

X² is N or CR²;

X³ is N or CR³;

X⁴ is N or CR⁴;

X⁵ is N or CR⁵;

X⁶ is N or CR⁶;

X³, X⁴, X⁵ and X⁶ are not simultaneously N;

R⁷ is H, methyl, or ethyl, wherein said methyl and ethyl are eachoptionally substituted with 1, 2 or 3 groups independently selected fromhalo, OH, oxo, CN, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, NH₂,C₁₋₆alkyl-NH—, and (C₁₋₆alkyl)₂N—;

R¹, R², R⁴, R⁵, R⁶ and R⁸ are each independently selected from H, halo,C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy,C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, CN, NO₂, OR^(a1), C(O)R^(a1),C(O)NR^(a1)R^(a1), C(O)OR^(a1), OC(O)R^(a1), OC(O)NR^(a1)R^(a1),NR^(a1)R^(a1), NR^(a1)C(O)R^(a1), NR^(a1)C(O)OR^(a1),NR^(a1)C(O)NR^(a1)R^(a1), NR^(a1)S(O)R^(a1), NR^(a1)S(O)₂R^(a1),NR^(a1)S(O)₂NR^(a1)R^(a1), S(O)R^(a1), S(O)NR^(a1)R^(a1), S(O)₂R^(a1),and S(O)₂NR^(a1)R^(a1), wherein the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- of R¹, R², R³, R⁴, R⁵, R⁶ and R⁸ are eachoptionally substituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

R³ is H, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, OH,CN, NH₂, C₁₋₆ alkyl-NH—, or (C₁₋₆alkyl)₂N—;

R⁹ is H, CN, NH₂, —OH, —COOH, —NH(C₁₋₆alkyl), —NH(C₁₋₆alkyl)₂,C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy or C₁₋₆haloalkoxy, wherein theC₁₋₆alkyl is optionally substituted with 1, 2 or 3 independentlyselected R^(q) substituents;

R¹⁰ is selected from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆haloalkoxy, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄alkyl-, OR^(a2), C(O)R^(a2),C(O)NR^(a2)R^(a2), C(O)OR^(a2), NR^(a2)R^(a2). NR^(a2)C(O)R^(a2),NR^(a2)C(O)OR^(a2), NR^(a2)C(O)NR^(a2)R^(a2), NR^(a2)S(O)R^(a2),NR^(a2)S(O)₂R^(a2), NR^(a2)S(O)₂NR^(a2)R^(a2), S(O)R^(a2), S(O)₂R^(a2),wherein the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- of R¹⁰ are each optionally substituted with1, 2, 3, 4 or 5 independently selected R^(b) substituents;

L is

wherein each R¹¹ is independently H or C₁₋₆alkyl optionally substitutedwith 1 or 2 R^(q) substituents and wherein the single wavy lineindicates the point of attachment to R¹⁰ and the double wavy lineindicates the point of attachment to the 6-membered ring A;

R^(a1) and R^(a2) are each independently selected from H, C₁₋₆alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 memberedheteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-,wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- of R^(a1) and R^(a2) are each optionallysubstituted with 1, 2, 3, 4, or 5 independently selected R^(d)substituents;

each R^(b) substituent is independently selected from halo, C₁₋₄alkyl,C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 memberedheteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, CN,NO₂, OR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) orS(O)₂NR^(c)R^(c); wherein the C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄haloalkoxy,C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- of R^(b) are each further optionallysubstituted with 1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆alkyl, C₁₋₄haloalkyl,C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl-;

each R^(d) is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,halo, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10membered heterocycloalkyl)-C₁₋₄alkyl-, CN, OR^(e), C(O)R^(e),C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NR^(e)R^(e),NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e);

each R^(e) is independently selected from H, CN, C₁₋₆alkyl,C₁₋₄haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 memberedheteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-;

or any two R^(a1) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3independently selected R^(h) substituents;

or any two R^(a2) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3independently selected R^(h) substituents;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

each R^(h) is independently selected from C₁₋₆alkyl, C₃₋₁₀cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄alkyl-, C₁₋₆haloalkyl, C₂₋₆ alkenyl,C₂₋₆alkynyl, halo, CN, OR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i),OC(O)R^(i), OC(O)NR^(i)R^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), S(O)R^(i), S(O)NR^(i)R^(i),S(O)₂R^(i), NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), andS(O)₂NR^(i)R^(i)

each R^(i) is independently selected from H, C₁₋₄alkyl, C₃₋₆cycloalkyl,C₆₋₁₀aryl, 5 or 6-membered heteroaryl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl;

each R^(q) is independently selected from OH, CN, —COOH, NH₂, halo,C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₄alkylthio,phenyl, 5-6 membered heteroaryl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, —CONHR¹², —NHC(O)R¹², —OC(O)R¹², —C(O)OR¹², —C(O)R¹²,—SO₂R¹², —NHSO₂R¹², —SO₂NHR¹² and NR¹²R¹²; and

each R¹² is independently C₁₋₆alkyl.

In some embodiments, one or more hydrogen atoms in a compound of thepresent disclosure (e.g., a compound of Formula I, II, III, IV, V, andthe like), or a pharmaceutically acceptable salt thereof, can bereplaced by one or more deuterium atoms. In some embodiments, one ormore hydrogen atoms in a C₁₋₆alkyl group can be replaced by deuteriumatoms (e.g., —CDs).

In some embodiments, X¹ is N.

In some embodiments, X¹ is CR¹.

In some embodiments, X² is N.

In some embodiments, X² is CR².

In some embodiments, X³ is N.

In some embodiments, X³ is CR³.

In some embodiments, X⁴ is N.

In some embodiments, X⁴ is CR⁴.

In some embodiments, X⁴ is CH.

In some embodiments, X⁵ is N.

In some embodiments, X⁵ is CR⁵.

In some embodiments, X⁵ is CH.

In some embodiments, X⁴ is CH and X⁵ is CH or N.

In some embodiments, X⁶ is N.

In some embodiments, X⁶ is CR⁶.

In some embodiments, R¹ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionallysubstituted by 1, 2, 3, 4, or 5 independently selected R^(b)substituents.

In some embodiments, R¹ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl, wherein the C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl are each optionallysubstituted by 1, 2, 3, 4, or 5 independently selected R^(b)substituents.

In some embodiments, R¹ is H, halo, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein theC₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl are each optionally substituted by 1, 2, 3, 4, or 5independently selected R^(b) substituents.

In some embodiments, R¹ is H, halo, or 5-10 membered heteroaryl, whereinthe 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, or5 independently selected R^(b) substituents.

In some embodiments, R¹ is H, halo, or 5-10 membered heteroaryl, whereinthe 5-10 membered heteroaryl is optionally substituted by 1 or 2independently selected R^(b) substituents.

In some embodiments, R¹ is H, halo, or 5-6 membered heteroaryl, whereinthe 5-6 membered heteroaryl is optionally substituted by 1 or 2independently selected R^(b) substituents.

In some embodiments, R¹ is H, halo, or 5-6 membered heteroaryl, whereinthe 5-6 membered heteroaryl is optionally substituted by 1 or 2independently selected C₁₋₄alkyl groups.

In some embodiments, R¹ is H, C₁, or 1-methyl-1H-pyrazol-4-yl.

In some embodiments, R² is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, or C₁₋₆ haloalkyl, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, 4 or 5independently selected R^(b) substituents.

In some embodiments, R² is H.

In some embodiments, R³ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, or C₁₋₆ haloalkyl, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, 4 or 5independently selected R^(b) substituents.

In some embodiments, R³ is H.

In some embodiments, R⁴ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, or C₁₋₆ haloalkyl, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl are optionally substituted by 1, 2, 3, 4, or 5independently selected R^(b) substituents.

In some embodiments, R⁴ is H, halo, C₁₋₆alkyl, or C₁₋₆haloalkyl, whereinthe C₁₋₆alkyl is optionally substituted by 1, 2, 3, 4, or 5independently selected R^(b) substituents.

In some embodiments, R⁴ is H, halo, or C₁₋₆alkyl, wherein the C₁₋₆alkylis optionally substituted by 1, 2, 3, 4, or 5 independently selectedR^(b) substituents.

In some embodiments, R⁴ is H, D, F, Cl, CD₃, or methyl.

In some embodiments, R⁴ is H, F, Cl, CD₃, or methyl.

In some embodiments, R⁴ is H, F, CD₃, or methyl.

In some embodiments, R⁴ is H, F, or methyl.

In some embodiments, R⁴ is Cl, CD₃, or methyl.

In some embodiments, R⁴ is CD₃, or methyl.

In some embodiments, R⁵ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, or C₁₋₆ haloalkyl, wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl are each optionally substituted by 1, 2, 3, 4, or 5independently selected R^(b) substituents.

In some embodiments, R⁵ is H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, orC₁₋₆haloalkyl, wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylare each optionally substituted by 1, 2, 3, 4, or 5 independentlyselected R^(b) substituents.

In some embodiments, R⁵ is H, halo, C₁₋₆alkyl, or C₁₋₆haloalkyl, whereinthe C₁₋₆alkyl is optionally substituted by 1, 2, 3, 4, or 5independently selected R^(b) substituents.

In some embodiments, R⁵ is H, C₁₋₆alkyl, or C₁₋₆haloalkyl, wherein theC₁₋₆alkyl is optionally substituted by 1, 2, 3, 4, or 5 independentlyselected R^(b) substituents.

In some embodiments, R⁵ is H or C₁₋₆alkyl, wherein the C₁₋₆alkyl isoptionally substituted by 1, 2, 3, 4, or 5 independently selected R^(b)substituents.

In some embodiments, R⁵ is H or C₁₋₆alkyl.

In some embodiments, R⁵ is H or methyl.

In some embodiments, R⁵ is H or F.

In some embodiments, R⁴ is H and R⁵ is H.

In some embodiments, R⁶ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(a1), C(O)NR^(a1)R^(a1),C(O)OR^(a1), OC(O)R^(a1), OC(O)NR^(a1)R^(a1), NR^(a1)R^(a1),NR^(a1)C(O)R^(a1), NR^(a1)C(O)OR^(a1), NR^(a1)C(O)NR^(a1)R^(a1),C(═NR^(a1))R^(a1), C(═NR^(a1))NR^(a1)R^(a1),NR^(a1)C(═NR^(a1))NR^(a1)R^(a1), NR^(a1)C(═NOH)NR^(a1)R^(a1),NR^(a1)C(═NCN)NR^(a1)R^(a1), NR^(a1)S(O)R^(a1), NR^(a1)S(O)₂R^(a1),NR^(a1)S(O)₂NR^(a1)R^(a1), S(O)R^(a1), S(O)NR^(a1)R^(a1), S(O)₂R^(a1),SF₅, —P(O)R^(a1)R^(a1), —P(O)(OR^(a1))(OR^(a1)) and S(O)₂NR^(a1)R^(a1),wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionallysubstituted by 1, 2, 3, 4, or 5 independently selected R^(b)substituents.

In some embodiments, R⁶ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, CN, NO₂, OR^(a1), C(O)R^(a1), C(O)NR^(a1)R^(a1),C(O)OR^(a1), OC(O)R^(a1), OC(O)NR^(a1)R^(a1), NR^(a1)R^(a1),NR^(a1)C(O)R^(a1), NR^(a1)C(O)OR^(a1), NR^(a1)C(O)NR^(a1)R^(a1),NR^(a1)S(O)R^(a1), NR^(a1)S(O)₂R^(a1), NR^(a1)S(O)₂NR^(a1)R^(a1),S(O)R^(a1), S(O)NR^(a1)R^(a1), S(O)₂R^(a1), and S(O)₂NR^(a1)R^(a1),wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionallysubstituted by 1, 2, 3, 4, or 5 independently selected R^(b)substituents.

In some embodiments, R⁶ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, OR^(a1), SR^(a1), C(O)R^(a1), C(O)NR^(a1)R^(a1),C(O)OR^(a1), OC(O)R^(a1), or OC(O)NR^(a1)R^(a1), wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionally substituted by 1, 2, 3, 4,or 5 independently selected R^(b) substituents.

In some embodiments, R⁶ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, or OR^(a1), wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl are optionally substituted by 1, 2, 3, 4, or 5independently selected R^(b) substituents.

In some embodiments, R⁶ is H, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, orOR^(a1), wherein said C₁₋₆ alkyl is optionally substituted by 1, 2, 3,4, or 5 independently selected R^(b) substituents.

In some embodiments, R⁶ is H, halo, C₁₋₆alkyl, or OR^(a1), wherein saidC₁₋₆alkyl is optionally substituted by 1, 2, 3, 4, or 5 independentlyselected R^(b) substituents.

In some embodiments, R⁶ is H, halo, C₁₋₆alkyl, or OR^(a1).

In some embodiments, R⁶ is H, F, Cl, methyl, methoxy, or ethoxy.

In some embodiments, R⁶ is halo, C₁₋₆alkyl, or CN.

In some embodiments, R⁷ is H or C₁₋₆alkyl optionally substituted with 1,2 or 3 groups independently selected from halo, OH, oxo, CN, C₁₋₆alkoxy,and C₁₋₆haloalkoxy.

In some embodiments, R⁷ is H or C₁₋₆alkyl optionally substituted with 1,2 or 3 groups independently selected from OH and oxo.

In some embodiments, R⁷ is H, unsubstituted C₁₋₆alkyl, or C₁₋₆alkylsubstituted by oxo.

In some embodiments, R⁷ is H, unsubstituted C₁₋₂alkyl, or C₁₋₆alkylsubstituted by oxo.

In some embodiments, R⁷ is H, methyl, or ethyl, wherein said methyl orethyl are optionally substituted with 1, 2 or 3 groups independentlyselected from halo, OH, oxo, CN, C₁₋₆ alkoxy, and C₁₋₆haloalkoxy;

In some embodiments, R⁷ is H, methyl, or C(═O)CH₃.

In some embodiments, R⁷ is H.

In some embodiments, R⁸ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, or(4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents.

In some embodiments, R⁸ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, or(4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionallysubstituted with 1, 2, or 3 independently selected R^(q) substituents.

In some embodiments, R⁸ is H, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C M alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- are each optionally substituted with 1, 2,3, 4 or 5 independently selected R^(b) substituents.

In some embodiments, R⁸ is H, halo, C₁₋₆alkyl, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- are each optionally substituted with 1, 2,3, 4 or 5 independently selected R^(b) substituents.

In some embodiments, R⁸ is H, halo, C₁₋₆alkyl, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl- are each optionally substituted with 1, 2,or 3 independently selected R^(q) substituents.

In some embodiments, R⁸ is H, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₆₋₁₀aryl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, or (4-10membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, C₆₋₁₀aryl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10membered heterocycloalkyl)-C₁₋₄alkyl- are each optionally substitutedwith 1, 2, 3, 4 or 5 independently selected R^(b) substituents.

In some embodiments, R⁸ is H, halo, C₁₋₆alkyl, C₆₋₁₀aryl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, (5-10membered heteroaryl)-C₁₋₄alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, C₆₋₁₀aryl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10membered heterocycloalkyl)-C₁₋₄alkyl- are each optionally substitutedwith 1, 2, 3, 4 or 5 independently selected R^(b) substituents.

In some embodiments, R⁸ is H, halo, C₁₋₆alkyl, C₆₋₁₀aryl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, (5-10membered heteroaryl)-C₁₋₄alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, C₆₋₁₀aryl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10membered heterocycloalkyl)-C₁₋₄alkyl- are each optionally substitutedwith 1, 2, or 3 independently selected R^(q) substituents.

In some embodiments, R⁸ is H, halo, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6 memberedheterocycloalkyl, wherein the C₁₋₆alkyl, phenyl, 5-6 memberedheteroaryl, and 5-6 membered heterocycloalkyl each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents.

In some embodiments, R⁸ is H, halo, C₁₋₆alkyl, phenyl, 5-6 memberedheteroaryl, or 5-6 membered heterocycloalkyl, wherein the C₁₋₆alkyl,phenyl, 5-6 membered heteroaryl, and 5-6 membered heterocycloalkyl eachoptionally substituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents.

In some embodiments, R⁸ is H, halo, C₁₋₆alkyl, phenyl, 5-6 memberedheteroaryl, or 5-6 membered heterocycloalkyl, wherein the C₁₋₆alkyl,phenyl, 5-6 membered heteroaryl, and 5-6 membered heterocycloalkyl eachoptionally substituted with 1, 2, or 3 independently selected R^(q)substituents.

In some embodiments, R⁸ is halo, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₆cycloalkyl, C₆₋₁₀aryl or 5-6 membered heteroaryl, wherein C₁₋₆alkyl,C₆₋₁₀aryl and 5-6 membered heteroaryl are each optionally substitutedwith 1, 2 or 3 independently selected R^(b) substituents.

In some embodiments, R⁸ is halo, C₁₋₆alkyl, C₆₋₁₀aryl or 5-6 memberedheteroaryl, wherein C₁₋₆alkyl, C₆₋₁₀aryl and 5-6 membered heteroaryl areeach optionally substituted with 1, 2 or 3 independently selected R^(b)substituents.

In some embodiments, R⁸ is halo, C₁₋₆alkyl, C₆₋₁₀aryl or 5-6 memberedheteroaryl, wherein C₁₋₆alkyl, C₆₋₁₀aryl and 5-6 membered heteroaryl areeach optionally substituted with 1, 2, or 3 independently selected R^(q)substituents.

In some embodiments, R⁸ is halo, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₆cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein C₁₋₆alkyl,phenyl, and 5-6 membered heteroaryl are each optionally substituted with1, 2 or 3 R^(b) substituents.

In some embodiments, R⁸ is halo, C₁₋₆alkyl, phenyl, or 5-6 memberedheteroaryl, wherein C₁₋₆alkyl, phenyl, and 5-6 membered heteroaryl areeach optionally substituted with 1, 2 or 3 R^(b) substituents.

In some embodiments, R⁸ is halo, C₁₋₆alkyl, phenyl, or 5-6 memberedheteroaryl, wherein C₁₋₆alkyl, phenyl, and 5-6 membered heteroaryl areeach optionally substituted with 1, 2, or 3 independently selected R^(q)substituents.

In some embodiments, R⁸ is H, halo, C₁₋₆alkyl, or C₁₋₆haloalkyl.

In some embodiments, R⁸ is H, halo, or C₁₋₆alkyl.

In some embodiments, R⁸ is H, C₁, F, Br, methyl, or ethyl.

In some embodiments, R⁸ is phenyl, which is optionally substituted with1, 2, 3, 4 or 5 independently selected R^(b) substituents.

In some embodiments, R⁸ is phenyl, which is optionally substituted with1 or 2 independently selected R^(b) substituents.

In some embodiments, R⁸ is phenyl, which is optionally substituted with1, 2, or 3 independently selected R^(q) substituents.

In some embodiments, R⁸ is phenyl, which is optionally substituted with1 or 2 independently selected R^(b) substituents selected from halo,C₁₋₄alkyl, C₁₋₄haloalkyl, CN, NO₂, OR^(c), SR^(c), C(O)R^(c),C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c),C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NOH)NR^(c)R^(c), NR^(c)C(═NCN)NR^(c)R^(c), SF₅,—P(O)R^(c)R^(c), —P(O)(OR^(c))(OR^(c)), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c).

In some embodiments, R⁸ is phenyl, which is optionally substituted with1 or 2 independently selected R^(b) substituents independently selectedfrom halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(c), SR^(c),C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c),NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c),NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c),S(O)NR^(c)R^(c), S(O)₂R^(c) and S(O)₂NR^(c)R^(c).

In some embodiments, R⁸ is phenyl, which is optionally substituted with1 or 2 independently selected R^(b) substituents independently selectedfrom halo, C₁₋₄alkyl, C₁₋₄haloalkyl, CN, NR^(c)R^(c), NO₂, OR^(c),S(O)R^(c), S(O)₂R^(c), and S(O)₂NR^(c)R^(c).

In some embodiments, R⁸ is phenyl, which is optionally substituted with1 or 2 independently selected R^(b) substituents independently selectedfrom halo, C₁₋₄alkyl, CN, OR^(c), and S(O)₂R^(c).

In some embodiments, R⁸ is phenyl, which is optionally substituted with1 or 2 independently selected R^(b) substituents independently selectedfrom halo, C₁₋₄alkyl, CN, OR^(c), and S(O)₂R^(c), wherein each R^(c) isan independently selected C₁₋₆alkyl group.

In some embodiments, R⁸ is phenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,4-cyanophenyl, or 2-fluoro-3-methoxyphenyl.

In some embodiments, R⁸ is a 5-6 membered heteroaryl or 5-6 memberedheterocycloalkyl, wherein the 5-6 membered heteroaryl and 5-6 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, 4 or 5independently selected R^(b) substituents.

In some embodiments, R⁸ is a 5-6 membered heteroaryl, which isoptionally substituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents.

In some embodiments, R⁸ is a 5-6 membered heteroaryl, which isoptionally substituted with 1 or 2 independently selected R^(b)substituents.

In some embodiments, R⁸ is a 5-6 membered heteroaryl, which isoptionally substituted with 1 or 2 independently selected R^(b)substituents selected from halo, C₁₋₄alkyl, C₁₋₄haloalkyl, CN, NO₂,OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NOH)NR^(c)R^(c), NR^(c)C(═NCN)NR^(c)R^(c), SF₅,—P(O)R^(c)R^(c), —P(O)(OR^(c))(OR^(c)), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c).

In some embodiments, R⁸ is a 5-6 membered heteroaryl, which isoptionally substituted with 1 or 2 independently selected R^(b)substituents selected from halo, C₁₋₄alkyl, C₁₋₄haloalkyl, CN, NO₂,OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) andS(O)₂NR^(c)R^(c).

In some embodiments, R⁸ is a 5-6 membered heteroaryl, which isoptionally substituted with 1 or 2 independently selected R^(b)substituents selected from halo, C₁₋₄alkyl, C₁₋₄haloalkyl, CN,NR^(c)R^(c), NO₂, OR^(c), S(O)R^(c), S(O)₂R^(c), and S(O)₂NR^(c)R^(c).

In some embodiments, R⁸ is a 5-6 membered heteroaryl, which isoptionally substituted with 1 or 2 independently selected R^(b)substituents selected from C₁₋₄alkyl and C₁₋₄haloalkyl.

In some embodiments, R⁸ is a 5-6 membered heteroaryl, which isoptionally substituted with 1 or 2 independently selected R^(b)substituents selected from C₁₋₄alkyl.

In some embodiments, R⁸ is 2-fluoro-pyridin-3-yl, pyridin-4-yl,2-thienyl, 2-fluoro-5-(N-methylaminocarbonyl)phenyl,3-methylsulfonylphenyl, 2-fluoro-6-methoxyphenyl,1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl, pyrimidin-5-yl, or2-methylthiazol-5-yl.

In some embodiments, R⁸ is H, Br, Cl, C₁₋₄alkyl, phenyl,1H-pyrazol-3-yl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl or pyrimidinyl, whereinthe phenyl, 1H-pyrazol-3-yl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl and pyrimidinyl are eachoptionally substituted with 1 or 2 substituents independently selectedfrom halo, CN, —S(O)₂—C₁₋₆alkyl, C₁₋₆alkyl, and —C₁₋₆ alkylene-OH.

In some embodiments, R⁸ is H, Br, Cl, C₁₋₄alkyl, phenyl,1H-pyrazol-5-yl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl,1-methyl-1H-pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl orpyrimidinyl, wherein the phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, thiazol-5-yl,pyridyl, thiophenyl and pyrimidinyl are each optionally substituted with1 or 2 substituents independently selected from halo, CN,—S(O)₂—C₁₋₆alkyl, C₁₋₆ alkyl, and —C₁₋₆alkylene-OH.

In some embodiments, R⁸ is H, Br, Cl, C₁₋₄alkyl, C₁₋₄haloalkyl,cyclopropyl, phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, thiazol-5-yl,isoxazol-4-yl, isoxazol-5-yl, pyridyl, thiophenyl or pyrimidinyl,wherein the C₁₋₄alkyl, phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, thiazol-5-yl,isoxazol-4-yl, isoxazol-5-yl, pyridyl, thiophenyl and pyrimidinyl areeach optionally substituted with 1 or 2 independently selected R^(b)substituents.

In some embodiments, R⁸ is H, Br, Cl, C₁₋₄alkyl, phenyl,1H-pyrazol-5-yl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl,1-methyl-1H-pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl orpyrimidinyl, wherein the phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, thiazol-5-yl,pyridyl, thiophenyl and pyrimidinyl are each optionally substituted with1 or 2 independently selected R^(b) substituents.

In some embodiments, R⁸ is H, Br, Cl, C₁₋₄alkyl, phenyl,1H-pyrazol-5-yl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl,1-methyl-1H-pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl orpyrimidinyl, wherein the phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, thiazol-5-yl,pyridyl, thiophenyl and pyrimidinyl are each optionally substituted with1 or 2 independently selected R^(q) substituents.

In some embodiments, R⁸ is H, D, CD₃, CF₃, methyl, C(O)NR^(a1)R^(a1),C₃₋₆cycloalkyl, C₆₋₁₀ aryl, or 4-10 membered heterocycloalkyl, whereinthe C₆₋₁₀aryl and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1 or 2 independently selected R^(b) substituents.

In some embodiments, R⁸ is H, D, CD₃, CF₃, methyl, C(O)NR^(a1)R^(a1),cyclopropyl, phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, thiazol-5-yl,isoxazol-4-yl, isoxazol-5-yl, pyridyl, thiophenyl or pyrimidinyl,wherein the phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, thiazol-5-yl,isoxazol-4-yl, isoxazol-5-yl, pyridyl, thiophenyl and pyrimidinyl areeach optionally substituted with 1 or 2 independently selected R^(b)substituents.

In some embodiments, R⁸ is H, D, CD₃, CF₃, methyl, C(O)NR^(a1)R^(a1),cyclopropyl, phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, thiazol-5-yl,isoxazol-4-yl, isoxazol-5-yl, pyridyl, thiophenyl or pyrimidinyl,wherein the phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, thiazol-5-yl,isoxazol-4-yl, isoxazol-5-yl, pyridyl, thiophenyl and pyrimidinyl areeach optionally substituted with 1 or 2 independently selected R^(q)substituents.

In some embodiments, R⁸ is H, D, CD₃, CF₃, methyl, C(O)NR^(a1)R^(a1),C₃₋₆cycloalkyl, C₆₋₁₀ aryl, or 4-10 membered heterocycloalkyl, whereinthe C₆₋₁₀aryl and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1 or 2 independently selected R^(q) substituents.

In some embodiments, R⁸ is H, CF₃, or methyl.

In some embodiments, R⁹ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl,are each optionally substituted with 1, 2, 3, 4 or 5 independentlyselected R^(b) substituents.

In some embodiments, R⁹ is H.

In some embodiments, R² and R³ are each H.

In some embodiments, R² and R⁹ are each H.

In some embodiments, R³ and R⁹ are each H.

In some embodiments, R², R³, and R⁹ are each H.

In some embodiments, R¹⁰ is H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, or(4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents.

In some embodiments, R¹⁰ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, or(4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents.

In some embodiments, R¹⁰ is C₁₋₆alkyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 memberedheteroaryl)-C₁₋₄alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-,wherein the C₁₋₆alkyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents.

In some embodiments, R¹⁰ is C₁₋₆alkyl, phenyl, C₃₋₆cycloalkyl. 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-C₁₋₄alkyl-,C₃₋₆cycloalkyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl-, or (4-6membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, phenyl,C₃₋₆cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl,phenyl-C₁₋₄ alkyl-, C₃₋₆cycloalkyl-C₁₋₄alkyl-, (5-6 memberedheteroaryl)-C₁₋₄alkyl-, and (4-6 membered heterocycloalkyl)-C₁₋₄alkyl-are each optionally substituted with 1, 2, 3, 4 or 5 independentlyselected R^(b) substituents.

In some embodiments, R¹⁰ is C₁₋₆alkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₄alkyl-, 4-6 membered heterocycloalkyl or 4-6 memberedheterocycloalkyl-C₁₋₄alkyl-, each of which is optionally substitutedwith 1, 2 or 3 independently selected R^(b) substituents.

In some embodiments, R¹⁰ is C₁₋₆alkyl, C₃₋₆cycloalkyl, 4-6 memberedheterocycloalkyl, or (4-6 membered heterocycloalkyl)-C₁₋₄alkyl-, whereinthe C₁₋₆alkyl, phenyl, C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl,and (4-6 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents.

In some embodiments, R¹⁰ is C₁₋₆alkyl, which is optionally substitutedwith 1, 2, 3, 4 or 5 independently selected R^(b) substituents.

In some embodiments, R¹⁰ is C₁₋₆alkyl, which is optionally substitutedwith 1 or 2 independently selected R^(b) substituents.

In some embodiments, R¹⁰ is C₁₋₆alkyl, which is optionally substitutedwith 1 or 2 independently selected R^(b) substituents selected fromhalo, CN, NO₂, OR^(c), SR^(c), and NR^(c)R^(c).

In some embodiments, R¹⁰ is methyl, ethyl, or 3-hydroxypropyl.

In some embodiments, R¹⁰ is C₃₋₁₀cycloalkyl, which is optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents.

In some embodiments, R¹⁰ is C₃₋₆cycloalkyl, which is optionallysubstituted with 1 or 2 independently selected R^(b) substituents.

In some embodiments, R¹⁰ is C₃₋₆cycloalkyl, which is optionallysubstituted with 1 or 2 independently selected R^(b) substituentsselected from C₁₋₄alkyl, C₁₋₄haloalkyl, CN, NO₂, OR^(c), SR^(c),C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c),C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NOH)NR^(c)R^(c), NR^(c)C(═NCN)NR^(c)R^(c), SF₅,—P(O)R^(c)R^(c), —P(O)(OR^(c))(OR^(c)), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c); wherein the C₁₋₄alkyl of R^(b) isfurther optionally substituted with 1, 2, or 3 independently selectedR^(d) substituents selected from OR^(e).

In some embodiments, R¹⁰ is C₃₋₆cycloalkyl, which is optionallysubstituted with 1 or 2 independently selected R^(b) substituentsselected from C₁₋₄alkyl, C₁₋₄haloalkyl, CN, NO₂, OR^(c), C(O)R^(c),C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), NR^(c)R^(c),NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c),NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c),S(O)NR^(c)R^(c), S(O)₂R^(c) and S(O)₂NR^(c)R^(c); wherein the C₁₋₄alkylof R^(b) is further optionally substituted with 1, 2, or 3 independentlyselected R^(d) substituents selected from OR^(e).

In some embodiments, R¹⁰ is C₃₋₆cycloalkyl, which is optionallysubstituted with 1 or 2 independently selected R^(b) substituentsselected from C₁₋₄alkyl, OR^(a), NR^(c)R^(c), NR^(c)C(O)R^(c), andNR^(c)C(O)OR^(c), wherein the C₁₋₄alkyl of R^(b) is further optionallysubstituted with 1, 2, or 3 independently selected R^(d) substituentsselected from OR^(e).

In some embodiments, R¹⁰ is C₃₋₆cycloalkyl, which is optionallysubstituted with 1 or 2 independently selected R^(b) substituentsselected from C₁₋₄alkyl, OH, NH₂, NHC(O)R^(c), and NHC(O)OR^(c), whereinthe C₁₋₄alkyl is optionally substituted by OH, and each R^(c) is anindependently selected C₁₋₆alkyl group.

In some embodiments, R¹⁰ is cyclopropyl, 3-hydroxycyclobutyl,3-(hydroxymethyl)cyclobutyl, 4-hydroxycyclohexyl, 4-methoxycyclohexyl,4-aminocyclohexyl, 4-(N-(tert butoxycarbonyl)amino)cyclohexyl, or4-(N-(methylcarbonyl)amino)cyclohexyl.

In some embodiments, R¹⁰ is 4-10 membered heterocycloalkyl, or (4-15membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the 4-10 memberedheterocycloalkyl and (4-15 membered heterocycloalkyl)-C₁₋₄alkyl- areeach optionally substituted with 1, 2, 3, 4 or 5 independently selectedR^(b) substituents.

In some embodiments, R¹⁰ is 4-10 membered heterocycloalkyl, or (4-10membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the 4-10 memberedheterocycloalkyl and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- areeach optionally substituted with 1, 2, 3, 4 or 5 independently selectedR^(b) substituents.

In some embodiments, R¹⁰ is 4-10 membered heterocycloalkyl, or (4-10membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the 4-10 memberedheterocycloalkyl and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- areeach optionally substituted with 1, 2, or 3 independently selected R^(b)substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl, CN, NO₂, OR^(c),C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c),NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c),NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c),S(O)NR^(c)R^(c), S(O)₂R^(c) and S(O)₂NR^(c)R^(c), wherein each C₁₋₄alkylof R^(b) is further optionally substituted with 1, 2, or 3 independentlyselected R^(d) substituents.

In some embodiments, R¹⁰ is 4-6 membered heterocycloalkyl or (4-6membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the 4-6 memberedheterocycloalkyl and (4-6 membered heterocycloalkyl)-C₁₋₄alkyl- are eachoptionally substituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents.

In some embodiments, R¹⁰ is 4-6 membered heterocycloalkyl or (4-6membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the 4-6 memberedheterocycloalkyl and (4-6 membered heterocycloalkyl)-C₁₋₄alkyl- are eachoptionally substituted with 1 or 2 independently selected R^(b)substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl, CN, NO₂, OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NOH)NR^(c)R^(c), NR^(c)C(═NCN)NR^(c)R^(c), SF₅,—P(O)R^(c)R^(c), —P(O)(OR^(c))(OR^(c)), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c), wherein the C₁₋₄alkyl of R^(b) isfurther optionally substituted with 1, 2, or 3 independently selectedR^(d) substituents.

In some embodiments, R¹⁰ is 4-6 membered heterocycloalkyl or (4-6membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the 4-6 memberedheterocycloalkyl and (4-6 membered heterocycloalkyl)-C₁₋₄alkyl- are eachoptionally substituted with 1 or 2 independently selected R^(b)substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl, CN, NO₂, OR^(c),C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c),NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c),NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c),S(O)NR^(c)R^(c), S(O)₂R^(c) and S(O)₂NR^(c)R^(c), wherein the C₁₋₄alkylof R^(b) is further optionally substituted with 1, 2, or 3 independentlyselected R^(d) substituents.

In some embodiments, R¹⁰ is 4-6 membered heterocycloalkyl or (4-6membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the 4-6 memberedheterocycloalkyl and (4-6 membered heterocycloalkyl)-C₁₋₄alkyl- are eachoptionally substituted with 1 or 2 independently selected R^(b)substituents selected from C₁₋₄alkyl, OR^(a), NR^(c)R^(c),NR^(c)C(O)R^(c), and NR^(c)C(O)OR^(c), wherein the C₄₋₄alkyl of R^(b) isfurther optionally substituted with 1, 2, or 3 independently selectedR^(d) substituents.

In some embodiments, R¹⁰ is 4-6 membered heterocycloalkyl, or (4-6membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the 4-6 memberedheterocycloalkyl and (4-6 membered heterocycloalkyl)-C₁₋₄alkyl- are eachoptionally substituted with 1 or 2 independently selected R^(b)substituents selected from C₁₋₄alkyl and OR^(a), wherein the C₁₋₄alkylof R^(b) is further optionally substituted with 1, 2, or 3 independentlyselected R^(d) substituents selected from OR^(e).

In some embodiments, R¹⁰ is 4-6 membered heterocycloalkyl, or (4-6membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the 4-6 memberedheterocycloalkyl and (4-6 membered heterocycloalkyl)-C₁₋₄alkyl- are eachoptionally substituted with 1 or 2 independently selected R^(b)substituents selected from C₁₋₄alkyl and OH, wherein the C₁₋₄alkyl isoptionally substituted by OH.

In some embodiments, R¹⁰ is tetrahydro-2H-pyran-4-yl,4-hydroxypiperidin-1-yl, or 2-(hydroxymethyl)tetrahydro-1H-pyran-5-yl.

In some embodiments, R¹⁰ is methyl, ethyl, 3-hydroxypropyl,tetrahydrofuran-3-ylmethyl, 2-(3-oxetanyl)prop-1-yl, cyclopropyl,3-hydroxycyclobutyl, 3-(hydroxymethyl)cyclobutyl, 4-hydroxycyclohexyl,4-methoxycyclohexyl, 4-aminocyclohexyl, tetrahydro-2H-pyran-4-yl,4-hydroxypiperidin-1-yl, 4-(N-(tert butoxycarbonyl)amino)cyclohexyl,4-(N-(methylcarbonyl)amino)cyclohexyl, or2-(hydroxymethyl)tetrahydro-1H-pyran-5-yl, each of which is optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents.

In some embodiments, R¹⁰ is methyl, ethyl, 3-hydroxypropyl,tetrahydrofuran-3-ylmethyl, 2-(3-oxetanyl)prop-1-yl, cyclopropyl,3-hydroxycyclobutyl, 3-(hydroxymethyl)cyclobutyl, 4-hydroxycyclohexyl,4-methoxycyclohexyl, 4-aminocyclohexyl, tetrahydro-2H-pyran-4-yl,4-hydroxypiperidin-1-yl, 4-(N-(tert butoxycarbonyl)amino)cyclohexyl,4-(N-(methylcarbonyl)amino)cyclohexyl, or2-(hydroxymethyl)tetrahydro-1H-pyran-5-yl.

In some embodiments, R¹⁰ is methyl, ethyl, propyl, cyclopropyl,cyclobutyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, or—CH₂-oxetanyl, each of which is optionally substituted with 1 or 2independently selected R^(b) substituents

In some embodiments, R¹⁰ is methyl, ethyl, propyl, cyclopropyl,cyclobutyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, or—CH₂-oxetanyl, each of which is optionally substituted with 1 or 2independently selected R^(q) substituents.

In some embodiments, R¹⁰ is a bicyclic C₄₋₁₀cycloalkyl or a bicyclic4-10 membered heterocycloalkyl, each of which is optionally substitutedwith 1, 2, 3, 4 or 5 independently selected R^(b) substituents.

In some embodiments, R¹⁰ is a spirocyclic C₅₋₁₀ membered cycloalkyl or aspirocyclic 5-10 membered heterocycloalkyl, each of which is optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents.

In some embodiments, R¹⁰ is a bridged bicyclic C₅₋₁₀ membered cycloalkylor a bridged bicyclic 6-10 membered heterocycloalkyl, which isoptionally substituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents.

In some embodiments, R¹⁰ is selected from:

In some embodiments, R¹⁰ is selected from:

In some embodiments, R¹⁰ is

In some embodiments, L is

wherein each R¹¹ is independently H or C₁₋₆alkyl optionally substitutedwith 1 or 2 R^(q) substituents and wherein the single wavy lineindicates the point of attachment to R¹⁰ and the double wavy lineindicates the point of attachment to the 6-membered ring A.

In some embodiments, L is

wherein each R¹¹ is independently H or C₁₋₆alkyl.

In some embodiments, L is

wherein each R¹¹ is H or methyl.

In some embodiments, L is

and R¹¹ is H or C₁₋₆alkyl.

In some embodiments, L is

and R¹¹ is H or C₁₋₆alkyl.

In some embodiments, L is —SO₂—.

In some embodiments, L is

In some embodiments, L is

and R¹⁰ is H or C₁₋₆alkyl.

In some embodiments, -L-R¹⁰ forms a group selected from:

wherein each R^(a) is independently selected from H, D, halo, oxo,C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₄haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-14 memberedheterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, C₁₋₆alkoxy,C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-14 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and(4-14 membered heterocycloalkyl)-C₁₋₄alkyl- of R^(a1) and R^(a2) areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(d) substituents, and wherein R¹⁰ and R¹¹ taken together with thenitrogen atom to which they are attached, form a 4 to 14-memberedheterocycloalkyl (indicated by the dashed ring structure) having 0 to 4additional heteroatoms as a ring member, each of which is independentlyselected from N, O and S, wherein the 4 to 14-membered heterocycloalkylformed by R¹⁰, R¹¹ and N is optionally substituted with 1, 2, or 3independently selected R^(b) substituents.

In some embodiments, L is

and R¹⁰ and R¹¹ are taken together with the nitrogen atom to which theyare attached to form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-memberedheterocycloalkyl having 0 to 1 additional heteroatom as a ring memberselected from N, O and S, wherein the 4-, 5-, 6-, 7-, 8-, 9-, or10-membered heterocycloalkyl formed by R¹⁰, R¹¹ and N is optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents.

In some embodiments, L is

and R¹⁰ and R¹¹ are taken together with the nitrogen atom to which theyare attached to form a 8-, 9-, or 10-membered heterocycloalkyl having 0to 1 additional heteroatom as a ring member selected from N, O, and S,wherein the 8-, 9-, or 10-membered heterocycloalkyl formed by R¹⁰, R¹¹,and N is optionally substituted with 1, 2 or 3 independently selectedR^(q) substituents.

In some embodiments, -L-R¹⁰ forms a group selected from:

wherein X⁷, X⁸, X⁹ are each independently selected from be C, N, O, orS, wherein p, m and n are each independently 0, 1, 2, 3 or 4; andwherein each formed group is optionally substituted with 0, 1, 2, 3 or 4independently selected R^(b) substituents.

In some embodiments, X⁷, X⁸, X⁹ are each independently C, N or O.

In some embodiments, X⁸ and X⁹ are C, and X⁷ is selected from C, N or O.

In some embodiments, X⁸ and X⁹ are C, and X⁷ is selected from C or O.

In some embodiments, p, m, and n are each independently 0, 1 or 2.

In some embodiments, p, m, and n are each independently 1 or 2.

In some embodiments, -L-R¹⁰ forms a group selected from:

In some embodiments, one or more R^(b) groups of a compound providedherein is each an independently selected R^(q) group. In someembodiments, each R^(b) group of a compound provided herein is anindependently selected R^(q) group.

In some embodiments:

X¹ is N or CR¹;

X² is N or CR²;

X³ is CR³;

X⁴ is CR⁴;

X⁵ is N or CR⁵;

X⁶ is CR⁶;

R¹ is H, halo, or 5-10 membered heteroaryl, wherein said 5-10 memberedheteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independentlyselected R^(b) substituents;

R² is H;

R³ is H;

R⁴ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, or C₁₋₆haloalkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionallysubstituted by 1, 2, 3, 4, or 5 independently selected R^(b)substituents;

R⁵ is H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, or C₁₋₆haloalkyl, whereinsaid C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionallysubstituted by 1, 2, 3, 4, or 5 independently selected R^(b)substituents;

R⁶ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,OR^(a1), SR^(a1), C(O)R^(a1), C(O)NR^(a1)R^(a1), C(O)OR^(a1),OC(O)R^(a1), or OC(O)NR^(a1)R^(a1), wherein said C₁₋₆alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are optionally substituted by 1, 2, 3, 4, or 5independently selected R^(b) substituents;

R⁷ is H, methyl or ethyl, wherein said methyl and ethyl are eachoptionally substituted with 1, 2 or 3 groups independently selected fromhalo, OH, oxo, CN, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

R⁸ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

R⁹ is H;

R¹⁰ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

L is

each R¹¹ is independently H or C₁₋₆alkyl;

or when L is

R¹⁰ and R¹¹ optionally taken together with the nitrogen atom to whichthey are attached, form a 4 to 14-membered heterocycloalkyl or a 4 to14-membered heterocycloalkyl-C₁₋₄alkyl-, having 0 to 4 additionalheteroatoms as a ring member, each of which is independently selectedfrom N, O and S, wherein the 4 to 14-membered heterocycloalkyl formed byR¹⁰, R¹¹ and N is optionally substituted with 1, 2 or 3 independentlyselected R^(b) substituents;

each R^(a1) is independently selected from H, C₁₋₆alkyl, C₁₋₄haloalkyl,C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-14 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and(4-14 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-14 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and(4-14 membered heterocycloalkyl)-C₁₋₄alkyl- of R^(a1) are eachoptionally substituted with 1, 2, 3, 4, or 5 R^(d) substituents;

each R^(b) substituent is independently selected from D, halo,C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, CN, OR^(c), C(O)R^(c),C(O)NR^(c)R^(c), OC(O)NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄alkyl, C₁₋₄ haloalkyl,and C₁₋₄haloalkoxy of R^(b) are each further optionally substituted with1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆alkyl, C₁₋₄haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(d) is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl, andOR^(e); and

each R^(e) is independently selected from H, C₁₋₆alkyl, C₁₋₄haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments:

X¹ is N or CR¹;

X² is N or CR²;

X³ is CR³;

X⁴ is CR⁴;

X⁵ is N or CR⁵;

X⁶ is CR⁶;

R¹ is H, halo, or 5-10 membered heteroaryl, wherein said 5-10 memberedheteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independentlyselected R^(b) substituents;

R² is H;

R³ is H;

R⁴ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, or C₁₋₆haloalkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionallysubstituted by 1, 2, 3, 4, or 5 independently selected R^(b)substituents;

R⁵ is H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, or C₁₋₆haloalkyl, whereinsaid C₁₋₆alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are optionally substitutedby 1, 2, 3, 4, or 5 independently selected R^(b) substituents;

R⁶ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,OR^(a1), SR^(a1), C(O)R^(a1), C(O)NR^(a1)R^(a1), C(O)OR^(a1),OC(O)R^(a1), or OC(O)NR^(a1)R^(a1), wherein said C₁₋₆alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are optionally substituted by 1, 2, 3, 4, or 5independently selected R^(b) substituents;

R⁷ is H, methyl or ethyl, wherein said methyl and ethyl are eachoptionally substituted with 1, 2 or 3 groups independently selected fromhalo, OH, oxo, CN, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

R⁸ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

R⁹ is H;

R¹⁰ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

L is

each R¹¹ is independently H or C₁₋₆alkyl;

or when L is

R¹⁰ and R¹¹ optionally taken together with the nitrogen atom to whichthey are attached, form 4-, 5-, 6- or 7-membered heterocycloalkyl having0 to 1 additional heteroatom as a ring member, which is selected from N,O and S, wherein the 4-, 5-, 6- or 7-membered heterocycloalkyl formed byR¹⁰, R¹¹ and N is optionally substituted with 1, 2 or 3 independentlyselected R^(q) substituents;

each R^(a1) is independently selected from H, C₁₋₆alkyl, C₁₋₄haloalkyl,C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- of R^(a1) are eachoptionally substituted with 1, 2, 3, 4, or 5 R^(d) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₄alkyl,C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, CN, OR^(c), C(O)R^(c), C(O)NR^(c)R^(c),OC(O)NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) orS(O)₂NR^(c)R^(c); wherein the C₁₋₄alkyl, C₁₋₄ haloalkyl, andC₁₋₄haloalkoxy of R^(b) are each further optionally substituted with 1,2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆alkyl, C₁₋₄haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(d) is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl, andOR^(e); and

each R^(e) is independently selected from H, C₁₋₆alkyl, C₁₋₄haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments:

X¹ is N or CR¹;

X² is N or CR²;

X³ is CR³;

X⁴ is CR⁴;

X⁵ is N or CR⁵;

X⁶ is CR⁶;

R¹ is H, halo, or 5-6 membered heteroaryl, wherein said 5-6 memberedheteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independentlyselected R^(b) substituents;

R² is H;

R³ is H;

R⁴ is H, halo, C₁₋₆alkyl, or C₁₋₆haloalkyl;

R⁵ is H, C₁₋₆alkyl, or C₁₋₆haloalkyl;

R⁶ is H, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, OR^(a1), SR^(a1), C(O)R^(a1),C(O)NR^(a1)R^(a1), C(O)OR^(a1), OC(O)R^(a1), or OC(O)NR^(a1)R^(a1),wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionallysubstituted by 1, 2, 3, 4, or 5 independently selected R^(b)substituents;

R⁷ is H, methyl or ethyl, wherein said methyl and ethyl are eachoptionally substituted with 1, 2 or 3 groups independently selected fromhalo, OH, oxo, CN, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

R⁸ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

R⁹ is H;

R¹⁰ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

L is

each R¹¹ is independently H or C₁₋₆alkyl;

or when L is

R¹⁰ and R¹¹ optionally taken together with the nitrogen atom to whichthey are attached, form a 4 to 6-membered heterocycloalkyl or a 4 to14-membered heterocycloalkyl-C₁₋₄alkyl-, having 0 to 1 additionalheteroatoms as a ring member, each of which is independently selectedfrom N, O and S, wherein the 4 to 6-membered heterocycloalkyl formed byR¹⁰, R¹¹ and N is optionally substituted with 1, 2 or 3 independentlyselected R^(b) substituents;

each R^(a1) is independently selected from H and C₁₋₆alkyl;

each R^(b) is independently selected from halo, C₁₋₄alkyl,C₃₋₆cycloalkyl, CN, OR^(c), C(O)NR^(c)R^(c), NR^(c)R^(c),NR^(c)C(O)OR^(c), S(O)R^(c), or S(O)₂R^(c); wherein the C₁₋₄alkyl ofR^(b) is further optionally substituted with 1, 2, or 3 independentlyselected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆alkyl, C₁₋₄haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(d) is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,OR^(e); and

each R^(e) is independently selected from H, C₁₋₆alkyl, C₁₋₄haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments:

X¹ is N or CR¹;

X² is N or CR²;

X³ is CR³;

X⁴ is CR⁴;

X⁵ is N or CR⁵;

X⁶ is CR⁶;

R¹ is H, halo, or 5-6 membered heteroaryl, wherein said 5-6 memberedheteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independentlyselected R^(b) substituents;

R² is H;

R³ is H;

R⁴ is H, halo, C₁₋₆alkyl, or C₁₋₆haloalkyl;

R⁵ is H, C₁₋₆alkyl, or C₁₋₆haloalkyl;

R⁶ is H, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, OR^(a1), SR^(a1), C(O)R^(a1),C(O)NR^(a1)R^(a1), C(O)OR^(a1), OC(O)R^(a1), or OC(O)NR^(a1)R^(a1),wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionallysubstituted by 1, 2, 3, 4, or 5 independently selected R^(b)substituents;

R⁷ is H, methyl or ethyl, wherein said methyl and ethyl are eachoptionally substituted with 1, 2 or 3 groups independently selected fromhalo, OH, oxo, CN, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

R⁸ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl,C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and (4-10membered heterocycloalkyl)-C₁₋₄alkyl- are each optionally substitutedwith 1, 2, 3, 4 or 5 independently selected R^(b) substituents;

R⁹ is H;

R¹⁰ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

L is

each R¹¹ is independently H or C₁₋₆alkyl;

or when L is

R¹⁰ and R¹¹ optionally taken together with the nitrogen atom to whichthey are attached, form 4-, 5- or 6-membered heterocycloalkyl having 0to 1 additional heteroatom as a ring member, which is selected from N, Oand S, wherein the 4-, 5- or 6-membered heterocycloalkyl formed by R¹⁰,R¹¹ and N is optionally substituted with 1, 2 or 3 independentlyselected R^(q) substituents;

each R^(a1) is independently selected from H and C₁₋₆alkyl;

each R^(b) is independently selected from halo, C₁₋₄alkyl,C₃₋₆cycloalkyl, CN, OR^(c), C(O)NR^(c)R^(c), NR^(c)R^(c),NR^(c)C(O)OR^(c), S(O)R^(c), or S(O)₂R^(c); wherein the C₁₋₄alkyl ofR^(b) is further optionally substituted with 1, 2, or 3 independentlyselected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆alkyl, C₁₋₄haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(d) is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,OR^(e); and

each R^(e) is independently selected from H, C₁₋₆alkyl, C₁₋₄haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments:

X¹ is N or CR¹;

X² is N or CR²;

X³ is CR³;

X⁴ is CR⁴;

X⁵ is N or CR⁵;

X⁶ is CR⁶;

R¹ is H, halo, or 5-6 membered heteroaryl, wherein said 5-6 memberedheteroaryl is optionally substituted by 1 or 2 independently selectedC₁₋₄alkyl groups;

R² is H;

R³ is H;

R⁴ is H, halo, or C₁₋₆alkyl;

R⁵ is H or C₁₋₆alkyl;

R⁶ is H, halo, C₁₋₆alkyl, or OR^(a1);

R⁷ is H, methyl or ethyl, wherein said methyl and ethyl are eachoptionally substituted with 1, 2 or 3 groups independently selected fromhalo, OH, oxo, CN, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

R⁸ is halo, C₁₋₆alkyl, phenyl, or 5-6 membered heteroaryl, whereinC₁₋₆alkyl, C₆₋₁₀aryl and 5-6 membered heteroaryl are each optionallysubstituted with 1, 2 or 3 independently selected R^(b) substituents;

R⁹ is H;

R¹⁰ is C₁₋₆alkyl, C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, or (4-6membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, phenyl,C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, and (4-6 memberedheterocycloalkyl)-C₁₋₄alkyl- are each optionally substituted with 1, 2,3, 4 or 5 independently selected R^(b) substituents;

L is

R¹¹ is H or C₁₋₆alkyl;

or when L is

R¹⁰ and R¹¹ optionally taken together with the nitrogen atom to whichthey are attached, form a 4 to 6-membered heterocycloalkyl or a 4 to14-membered heterocycloalkyl-C₁₋₄alkyl-, having 0 to 1 additionalheteroatoms as a ring member, each of which is independently selectedfrom N, O and S, wherein the 4 to 6-membered heterocycloalkyl formed byR¹⁰, R¹¹ and N is optionally substituted with 1, 2 or 3 independentlyselected R^(b) substituents;

each R^(a1) is H or C₁₋₆alkyl;

each R^(b) substituent is independently selected from halo, C₁₋₄alkyl,CN, OR^(c), C(O)NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)OR^(c), S(O)R^(c),or S(O)₂R^(c); wherein the C₁₋₄alkyl of R^(b) is further optionallysubstituted with 1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H and C₁₋₆alkyl;

each R^(d) is independently selected from C₁₋₆alkyl and OR^(e); and

each R^(e) is independently selected from H and C₁₋₆alkyl.

In some embodiments:

X¹ is N or CR¹;

X² is N or CR²;

X³ is CR³;

X⁴ is CR⁴;

X⁵ is N or CR⁵;

X⁶ is CR⁶;

R¹ is H, halo, or 5-6 membered heteroaryl, wherein said 5-6 memberedheteroaryl is optionally substituted by 1 or 2 independently selectedC₁₋₄alkyl groups;

R² is H;

R³ is H;

R⁴ is H, halo, or C₁₋₆alkyl;

R⁵ is H or C₁₋₆alkyl;

R⁶ is H, halo, C₁₋₆alkyl, or OR^(a1);

R⁷ is H, methyl or ethyl, wherein said methyl and ethyl are eachoptionally substituted with 1, 2 or 3 groups independently selected fromhalo, OH, oxo, CN, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

R⁸ is halo, C₁₋₆alkyl, phenyl, or 5-6 membered heteroaryl, whereinC₁₋₆alkyl, C₆₋₁₀aryl and 5-6 membered heteroaryl are each optionallysubstituted with 1, 2 or 3 independently selected R^(b) substituents;

R⁹ is H;

R¹⁰ is C₁₋₆alkyl, C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, or (4-6membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, phenyl,C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, and (4-6 memberedheterocycloalkyl)-C₁₋₄alkyl- are each optionally substituted with 1, 2,3, 4 or 5 independently selected R^(b) substituents;

L is

R¹¹ is H or C₁₋₆alkyl;

or when L is

R¹⁰ and R¹¹ optionally taken together with the nitrogen atom to whichthey are attached, form a 4-, 5- or 6-membered heterocycloalkyl having 0to 1 additional heteroatom as a ring member, which is selected from N, Oand S, wherein the 4-, 5- or 6-membered heterocycloalkyl formed by R¹⁰,R¹¹ and N is optionally substituted with 1, 2 or 3 independentlyselected R^(q) substituents;

each R^(a1) is H or C₁₋₆alkyl;

each R^(b) substituent is independently selected from halo, C₁₋₄alkyl,CN, OR^(c), C(O)NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)OR^(c), S(O)R^(c),or S(O)₂R^(c); wherein the C₁₋₄alkyl of R^(b) is further optionallysubstituted with 1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H and C₁₋₆alkyl;

each R^(d) is independently selected from C₁₋₆alkyl and OR^(e); and

each R^(e) is independently selected from H and C₁₋₆alkyl.

In some embodiments:

X¹ is N or CR¹;

X² is N or CR²;

X³ is CR³;

X⁴ is CR⁴;

X⁵ is N or CR⁵;

X⁶ is CR⁶;

R¹ is H, halo, or pyrazolyl, wherein said pyrazolyl is optionallysubstituted by 1 or 2 independently selected C₁₋₄alkyl groups;

R² is H;

R³ is H;

R⁴ is H, F, CD₃, or methyl;

R⁵ is H or methyl;

R⁶ is H, F, C₁, methyl, methoxy, or ethoxy;

R⁷ is H, methyl, or —C(O)-methyl;

R⁸ is H, Br, Cl, C₁₋₄alkyl, phenyl, 1H-pyrazol-5-yl, pyrazol-4-yl,thiazol-5-yl, pyridyl, thiophenyl or pyrimidinyl, wherein the phenyl,1H-pyrazol-5-yl, 1H-pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl andpyrimidinyl are each optionally substituted with 1 or 2 independentlyselected R^(b) substituents;

R⁹ is H;

R¹⁰ is methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, or —CH₂-oxetanyl, each of which isoptionally substituted with 1 or 2 independently selected R^(b)substituents;

L is

R¹¹ is H or methyl;

or when L is

R¹⁰ and R¹¹ optionally taken together with the nitrogen atom to whichthey are attached, form 4-, 5- or 6-membered heterocycloalkyl having 0to 1 additional heteroatom as a ring member, which is selected from N, Oand S, wherein the 4-, 5- or 6-membered heterocycloalkyl formed by R¹⁰,R¹¹ and N is optionally substituted with 1, 2 or 3 independentlyselected R^(q) substituents;

each R^(a1) is H or C₁₋₆alkyl;

each R^(b) substituent is independently selected from halo, C₁₋₄alkyl,CN, OR^(c), C(O)NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)OR^(c), orS(O)₂R^(c); wherein the C₁₋₄alkyl of R^(b) is further optionallysubstituted with 1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H and C₁₋₆alkyl;

each R^(d) is independently OR^(e); and

each R^(e) is independently selected from H and C₁₋₆alkyl.

In some embodiments:

X¹ is N or CR¹;

X² is N or CR²;

X³ is CR³;

X⁴ is CR⁴;

X⁵ is N or CR⁵;

X⁶ is CR⁶;

R¹ is H, halo, or pyrazolyl, wherein said pyrazolyl is optionallysubstituted by 1 or 2 independently selected C₁₋₄alkyl groups;

R² is H;

R³ is H;

R⁴ is H, F, or methyl;

R⁵ is H or methyl;

R⁶ is H, F, Cl, methyl, methoxy, or ethoxy;

R⁷ is H, methyl, or —C(O)-methyl;

R⁸ is H, Br, Cl, C₁₋₄alkyl, phenyl, 1H-pyrazol-5-yl, pyrazol-4-yl,thiazol-5-yl, pyridyl, thiophenyl or pyrimidinyl, wherein the phenyl,1H-pyrazol-5-yl, 1H-pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl andpyrimidinyl are each optionally substituted with 1 or 2 independentlyselected R^(b) substituents;

R⁹ is H;

R¹⁰ is methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, or —CH₂-oxetanyl, each of which isoptionally substituted with 1 or 2 independently selected R^(b)substituents;

L is

R¹¹ is H or methyl;

or when L is

R¹⁰ and R¹¹ optionally taken together with the nitrogen atom to whichthey are attached, form 4-, 5- or 6-membered heterocycloalkyl having 0to 1 additional heteroatom as a ring member, which is selected from N, Oand S, wherein the 4-, 5- or 6-membered heterocycloalkyl formed by R¹⁰,R¹¹ and N is optionally substituted with 1, 2 or 3 independentlyselected R^(q) substituents;

each R^(a1) is H or C₁₋₆alkyl;

each R^(b) substituent is independently selected from halo, C₁₋₄alkyl,CN, OR^(c), C(O)NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)OR^(c), orS(O)₂R^(c); wherein the C₁₋₄alkyl of R^(b) is further optionallysubstituted with 1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H and C₁₋₆alkyl;

each R^(d) is independently OR^(e); and

each R^(e) is independently selected from H and C₁₋₆alkyl.

In some embodiments:

X¹ is N or CR¹;

X² is N or CR²;

X³ is CR³;

X⁴ is CR⁴;

X⁵ is N or CR⁵;

X⁶ is CR⁶;

R¹ is H, halo, or 5-10 membered heteroaryl, wherein said 5-10 memberedheteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independentlyselected R^(b) substituents;

R² is H;

R³ is H;

R⁴ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, or C₁₋₆haloalkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionallysubstituted by 1, 2, 3, 4, or 5 independently selected R^(b)substituents;

R⁵ is H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, or C₁₋₆haloalkyl, whereinsaid C₁₋₆alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are optionally substitutedby 1, 2, 3, 4, or 5 independently selected R^(b) substituents;

R⁶ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,OR^(a1), SR^(a1), C(O)R^(a1), C(O)NR^(a1)R^(a1), C(O)OR^(a1),OC(O)R^(a1), or OC(O)NR^(a1)R^(a1), wherein said C₁₋₆alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are optionally substituted by 1, 2, 3, 4, or 5independently selected R^(b) substituents;

R⁷ is H, methyl or ethyl, wherein said methyl and ethyl are eachoptionally substituted with 1, 2 or 3 groups independently selected fromhalo, OH, oxo, CN, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

R⁸ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

R⁹ is H;

R¹⁰ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

L is

each R¹¹ is independently H or C₁₋₆alkyl;

each R^(a1) is independently selected from H, C₁₋₆alkyl, C₁₋₄haloalkyl,C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- of R^(a1) are eachoptionally substituted with 1, 2, 3, 4, or 5 R^(d) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₄alkyl,C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, CN, OR^(c), C(O)R^(c), C(O)NR^(c)R^(c),OC(O)NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) orS(O)₂NR^(c)R^(c); wherein the C₁₋₄alkyl, C₁₋₄ haloalkyl, andC₁₋₄haloalkoxy of R^(b) are each further optionally substituted with 1,2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆alkyl, C₁₋₄haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(d) is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl, andOR^(e); and

each R^(e) is independently selected from H, C₁₋₆alkyl, C₁₋₄haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments:

X¹ is N or CR¹;

X² is N or CR²;

X³ is CR³;

X⁴ is CR⁴;

X⁵ is N or CR⁵;

X⁶ is CR⁶;

R¹ is H, halo, or 5-6 membered heteroaryl, wherein said 5-6 memberedheteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independentlyselected R^(b) substituents;

R² is H;

R³ is H;

R⁴ is H, halo, C₁₋₆alkyl, or C₁₋₆haloalkyl;

R⁵ is H, C₁₋₆alkyl, or C₁₋₆haloalkyl;

R⁶ is H, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, OR^(a1), SR^(a1), C(O)R^(a1),C(O)NR^(a1)R^(a1), C(O)OR^(a1), OC(O)R^(a1), or OC(O)NR^(a1)R^(a1),wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionallysubstituted by 1, 2, 3, 4, or 5 independently selected R^(b)substituents;

R⁷ is H, methyl or ethyl, wherein said methyl and ethyl are eachoptionally substituted with 1, 2 or 3 groups independently selected fromhalo, OH, oxo, CN, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

R⁸ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

R⁹ is H;

R¹⁰ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄alkyl-,C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

L is

each R¹¹ is independently H or C₁₋₆alkyl;

each R^(a1) is independently selected from H and C₁₋₆alkyl;

each R^(b) is independently selected from halo, C₁₋₄alkyl, CN, OR^(c),C(O)NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)OR^(c), S(O)R^(c), orS(O)₂R^(c); wherein the C₁₋₄alkyl of R^(b) is further optionallysubstituted with 1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆alkyl, C₁₋₄haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(d) is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,OR^(e); and

each R^(e) is independently selected from H, C₁₋₆alkyl, C₁₋₄haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments:

X¹ is N or CR¹;

X² is N or CR²;

X³ is CR³;

X⁴ is CR⁴;

X⁵ is N or CR⁵;

X⁶ is CR⁶;

R¹ is H, halo, or 5-6 membered heteroaryl, wherein said 5-6 memberedheteroaryl is optionally substituted by 1 or 2 independently selectedC₁₋₄alkyl groups;

R² is H;

R³ is H;

R⁴ is H, halo, or C₁₋₆alkyl;

R⁵ is H or C₁₋₆alkyl;

R⁶ is H, halo, C₁₋₆alkyl, or OR^(a1);

R⁷ is H, methyl or ethyl, wherein said methyl and ethyl are eachoptionally substituted with 1, 2 or 3 groups independently selected fromhalo, OH, oxo, CN, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

R⁸ is halo, C₁₋₆alkyl, phenyl, or 5-6 membered heteroaryl, whereinC₁₋₆alkyl, C₆₋₁₀aryl and 5-6 membered heteroaryl are each optionallysubstituted with 1, 2 or 3 independently selected R^(b) substituents;

R⁹ is H;

R¹⁰ is C₁₋₆alkyl, C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, or (4-6membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆alkyl, phenyl,C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, and (4-6 memberedheterocycloalkyl)-C₁₋₄alkyl- are each optionally substituted with 1, 2,3, 4 or 5 independently selected R^(b) substituents;

L is

R¹¹ is H or C₁₋₆alkyl;

each R^(a1) is independently H or C₁₋₆alkyl;

each R^(b) substituent is independently selected from halo, C₁₋₄alkyl,CN, OR^(c), C(O)NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)OR^(c), S(O)R^(c),or S(O)₂R^(c); wherein the C₁₋₄alkyl of R^(b) is further optionallysubstituted with 1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H and C₁₋₆alkyl;

each R^(d) is independently selected from C₁₋₆alkyl and OR^(e); and

each R^(e) is independently selected from H and C₁₋₆alkyl.

In some embodiments:

X¹ is N or CR¹;

X² is N or CR²;

X³ is CR³;

X⁴ is CR⁴;

X⁵ is N or CR⁵;

X⁶ is CR⁶;

R¹ is H, halo, or pyrazolyl, wherein said pyrazolyl is optionallysubstituted by 1 or 2 independently selected C₁₋₄alkyl groups;

R² is H;

R³ is H;

R⁴ is H, F, or methyl;

R⁵ is H or methyl;

R⁶ is H, F, C₁, methyl, methoxy, or ethoxy;

R⁷ is H, methyl, or —C(O)-methyl;

R⁸ is H, Br, Cl, C₁₋₄alkyl, phenyl, 1H-pyrazol-5-yl, pyrazol-4-yl,thiazol-5-yl, pyridyl, thiophenyl or pyrimidinyl, wherein the phenyl,1H-pyrazol-5-yl, 1H-pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl andpyrimidinyl are each optionally substituted with 1 or 2 independentlyselected R^(b) substituents;

R⁹ is H;

R¹⁰ is methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, or —CH₂-oxetanyl, each of which isoptionally substituted with 1 or 2 independently selected R^(b)substituents;

L is

R¹¹ is H or methyl;

each R^(a1) is independently H or C₁₋₆alkyl;

each R^(b) substituent is independently selected from halo, C₁₋₄alkyl,CN, OR^(c), C(O)NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)OR^(c), orS(O)₂R^(c); wherein the C₁₋₄alkyl of R^(b) is further optionallysubstituted with 1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H and C₁₋₆alkyl;

each R^(d) is independently OR^(e); and

each R^(e) is independently selected from H and C₁₋₆alkyl.

In the last four embodiments, L is preferably

wherein R¹¹ is H or methyl.

In some embodiments:

X¹ is N;

X² is N;

X³ is CH;

X⁴ is CR⁴;

X⁵ is CH;

X⁶ is CH;

R⁴ is H, D, F, or C₁₋₆alkyl, wherein one or more hydrogen atoms of theC₁₋₆alkyl group are replaced with deuterium atoms;

R⁷ is H;

R⁸ is H, Br, Cl, C₁₋₄alkyl, phenyl, 1H-pyrazol-5-yl, pyrazol-4-yl,thiazol-5-yl, pyridyl, thiophenyl or pyrimidinyl, wherein the phenyl,1H-pyrazol-5-yl, 1H-pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl andpyrimidinyl are each optionally substituted with 1 or 2 independentlyselected R^(b) substituents;

R⁹ is H;

R¹⁰ is 4-10 membered heterocycloalkyl or (4-10 memberedheterocycloalkyl)-C₁₋₄alkyl-, each of which may be optionallysubstituted with 1 or 2 independently selected R^(b) substituents;

L is

R¹¹ is H or C₁₋₆alkyl;

each R^(b) substituent is independently selected from halo, C₁₋₄alkyl,CN, OR^(c), C(O)NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)OR^(c), andS(O)₂R^(c); wherein the C₁₋₄alkyl of R^(b) is further optionallysubstituted with 1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H and C₁₋₆alkyl;

each R^(d) is independently OR^(e); and

each R^(e) is independently selected from H and C₁₋₆alkyl.

In some embodiments:

X¹ is N;

X² is N;

X³ is CH;

X⁴ is CR⁴;

X⁵ is CH;

X⁶ is CH;

R⁴ is H, D, F, or C₁₋₆alkyl, wherein one or more hydrogen atoms of theC₁₋₆alkyl group are replaced with deuterium atoms;

R⁷ is H;

R⁸ is H, Br, Cl, C₁₋₄alkyl, phenyl, 1H-pyrazol-5-yl, pyrazol-4-yl,thiazol-5-yl, pyridyl, thiophenyl or pyrimidinyl, wherein the phenyl,1H-pyrazol-5-yl, 1H-pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl andpyrimidinyl are each optionally substituted with 1 or 2 independentlyselected R^(b) substituents;

R⁹ is H;

R¹⁰ is a bicyclic 6-10 membered heterocycloalkyl, which is optionallysubstituted with 1 or 2 independently selected R^(b) substituents;

L is

R¹¹ is H or C₁₋₆alkyl;

each R^(b) substituent is independently selected from halo, C₁₋₄alkyl,CN, OR^(c), C(O)NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)OR^(c), andS(O)₂R^(c); wherein the C₁₋₄alkyl of R^(b) is further optionallysubstituted with 1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H and C₁₋₆alkyl;

each R^(d) is independently OR^(e); and

each R^(e) is independently selected from H and C₁₋₆alkyl.

In some embodiments:

X¹ is N;

X² is N;

X³ is CH;

X⁴ is CR⁴;

X⁵ is CH;

X⁶ is CH;

R⁴ is H, D, F, or C₁₋₆alkyl, wherein one or more hydrogen atoms of theC₁₋₆alkyl group are replaced with deuterium atoms;

R⁷ is H;

R⁸ is H, Br, Cl, C₁₋₄alkyl, phenyl, 1H-pyrazol-5-yl, pyrazol-4-yl,thiazol-5-yl, pyridyl, thiophenyl or pyrimidinyl, wherein the phenyl,1H-pyrazol-5-yl, 1H-pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl andpyrimidinyl are each optionally substituted with 1 or 2 independentlyselected R^(b) substituents;

R⁹ is H;

R¹⁰ is a bicyclic 6-10 membered heterocycloalkyl, which is optionallysubstituted with 1 or 2 independently selected R^(b) substituents;

L is

R¹¹ is H or C₁₋₆alkyl;

each R^(b) substituent is independently selected from halo, C₁₋₄alkyl,CN, OR^(c), C(O)NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)OR^(c), andS(O)₂R^(c); and

each R^(c) is independently selected from H and C₁₋₆alkyl.

In some embodiments:

X¹ is N;

X² is N;

X³ is CH;

X⁴ is CR⁴;

X⁵ is CH;

X⁶ is CH;

R⁴ is H, D, F, or C₁₋₆alkyl, wherein one or more hydrogen atoms of theC₁₋₆alkyl group are replaced with deuterium atoms;

R⁷ is H;

R⁸ is H, Br, Cl, C₁₋₄alkyl, phenyl, 1H-pyrazol-5-yl, pyrazol-4-yl,thiazol-5-yl, pyridyl, thiophenyl or pyrimidinyl, wherein the phenyl,1H-pyrazol-5-yl, 1H-pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl andpyrimidinyl are each optionally substituted with 1 or 2 independentlyselected R^(b) substituents;

R⁹ is H;

R¹⁰ is a bicyclic 6-10 membered heterocycloalkyl, which is optionallysubstituted with 1 or 2 independently selected R^(b) substituents;

L is

R¹¹ is H or C₁₋₆alkyl;

each R^(b) substituent is independently selected from halo, C₁₋₄alkyl,CN, OR^(c), C(O)NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)OR^(c), andS(O)₂R^(c); and

each R^(c) is independently selected from H and C₁₋₆alkyl;

In some embodiments, L is preferably

wherein R¹¹ is H or methyl.

In some embodiments, the compound is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (IV):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (V):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (IIa), (IIb),(IIc), (IId), (IIe), (IIf), (IIIa), (IIIb), (IIIc), (IIId), (IIIe),(IIIf), (IVa), (IVb), (IVc), (IVd), (IVe), (Va), (Vb), (Vc), (Vd), or(Ve):

or a pharmaceutically acceptable salt thereof.

In the each of the subformulas (II), (III), (IV), (V), (IIa), (IIb),(IIc), (IId), (IIe), (IIf), (IIIa), (IIIb), (IIIc), (IIId), (IIIc),(IIId), (IVa), (IVb), (IVc), (IVd), (IVe), (Va), (Vb), (Vc), (Vd), or(Ve), L is preferably

wherein R¹¹ is H or methyl.

In some embodiments, the compound is a compound of Formula IIg, IIh,IVg, or IVh:

or a pharmaceutically acceptable salt or a tautomer thereof.

In some embodiments of Formulas (IIg), (IIh), (IVg), and (IVh), L is

wherein R¹¹ is H or methyl.

In some embodiments of Formulas (IIg), (IIh), (IVg), and (IVh), R⁴ is H,D, F, or C₁₋₆ alkyl, wherein one or more hydrogen atoms of the C₁₋₆alkylgroup are replaced with deuterium atoms.

In some embodiments of Formulas (IIg), (IIh), (IVg), and (IVh), R⁴ is H,D, F, CD₃, or CH₃.

In some embodiments, the compound is a compound of Formula (VI):

or a pharmaceutically acceptable salt or a tautomer thereof.

In some embodiments, the compound is a compound of Formula (VII):

or a pharmaceutically acceptable salt or a tautomer thereof.

In some embodiments, the compound is a compound of Formula (VII),wherein

R⁴ is selected from H, D, F, Cl, CD₃, and methyl; and

R⁸ is selected H, D, CD₃, CF₃, methyl, C(O)NR^(a1)R^(a1), C₆₋₁₀aryl, and4-10 membered heterocycloalkyl, wherein the C₆₋₁₀aryl and 4-10 memberedheterocycloalkyl are each optionally substituted with 1 or 2independently selected R^(q) substituents.

In some embodiments, the compound is a compound of Formula (VII),wherein

R⁴ is selected from Cl, CD₃, or methyl;

R⁵ is selected from H or F; and

R⁶ is selected CN, halo or C₁₋₆alkyl.

In some embodiments, the compound is a compound of Formula (VIII):

or a pharmaceutically acceptable salt or a tautomer thereof.

In some embodiments, the compound is a compound of Formula (VIII),wherein

R⁴ is selected from Cl, CD₃, or methyl;

R⁵ is selected from H or F;

R⁸ is selected H, CF₃ or methyl;

X⁷, X⁸, and X⁹ are each independently selected from C, O, N or S; and

m, n, p are each independently 0, 1, 2, 3 or 4.

In some embodiments, the compound is a compound of Formula (IX):

or a pharmaceutically acceptable salt or a tautomer thereof.

In some embodiments, the compound is a compound of Formula (IX), wherein

R⁴ is selected from CD₃, or methyl;

R⁸ is selected H, CF₃ or methyl;

X⁷ is selected from C, O, N or S; and

N is 0, 1, 2, 3 or 4.

In some embodiments, the compound is a compound of Formula (X):

or a pharmaceutically acceptable salt or a tautomer thereof.

In some embodiments, the compound is a compound of Formula (X), wherein

X⁷ is selected from C or O; and

-   -   N is 1, 2 or 3.

In some embodiments, the compound is a compound of Formula (X), wherein

X⁷ is C; and

N is 1 or 2.

In some embodiments, the compound or pharmaceutically acceptable salt ofthe compound of Formula (I) provided herein is crystalline. As usedherein, “crystalline” or “crystalline form” is meant to refer to acertain lattice configuration of a crystalline substance. Differentcrystalline forms of the same substance typically have differentcrystalline lattices (e.g., unit cells) which are attributed todifferent physical properties that are characteristic of each of thecrystalline forms. In some instances, different lattice configurationshave different water or solvent content.

Different crystalline forms of the same compound or salt can havedifferent bulk properties relating to, for example, hygroscopicity,solubility, stability, and the like. Forms with high melting pointsoften have good thermodynamic stability which is advantageous inprolonging shelf-life drug formulations containing the solid form. Formswith lower melting points often are less thermodynamically stable, butare advantageous in that they have increased water solubility,translating to increased drug bioavailability. Forms that are weaklyhygroscopic are desirable for their stability to heat and humidity andare resistant to degradation during long storage.

The different crystalline forms can be identified by solid statecharacterization methods such as by X-ray powder diffraction (XRPD).Other characterization methods such as differential scanning calorimetry(DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS),and the like further help identify the form as well as help determinestability and solvent/water content.

An XRPD pattern of reflections (peaks) is typically considered afingerprint of a particular crystalline form. It is well known that therelative intensities of the XRPD peaks can widely vary depending on,inter alia, the sample preparation technique, crystal size distribution,various filters used, the sample mounting procedure, and the particularinstrument employed. In some instances, new peaks may be observed orexisting peaks may disappear, depending on the type of the instrument orthe settings. As used herein, the term “peak” refers to a reflectionhaving a relative height/intensity of at least about 5% of the maximumpeak height/intensity. Moreover, instrument variation and other factorscan affect the 2-theta values. Thus, peak assignments, such as thosereported herein, can vary by plus or minus about 0.2° (2-theta), and theterm “substantially” and “about” as used in the context of XRPD hereinis meant to encompass the above-mentioned variations.

In the same way, temperature readings in connection with DSC, TGA, orother thermal experiments can vary about ±3° C. depending on theinstrument, particular settings, sample preparation, etc. Accordingly, acrystalline form reported herein having a DSC thermogram “substantially”as shown in any of the Figures or the term “about” is understood toaccommodate such variation.

The present invention provides crystalline forms of certain compounds,or salts thereof. In some embodiments, the compound of Formula I is3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamide,or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention provides crystalline3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamidecharacterized, for example, by an XRPD profile substantially as shown inFIG. 1.

In some embodiments, crystalline3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamidehas at least one, at least two, at least three, at least four, or atleast five XRPD peaks, in terms of 2-theta, selected from about 8.4°,about 15.3°, about 16.9°, about 17.3°, about 17.4°, about 17.6°, about19.4°, about 20.6°, about 24.9°, and about 26.5°.

In some embodiments, crystalline3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamideis characterized by a DSC thermogram having an endothermic peak at about234° C.

In some embodiments, crystalline3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamideis characterized by a thermographic analysis (TGA) substantially asshown in FIG. 3.

In some embodiments, the3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamidecan be isolated as a hydrochloric acid salt, which can be crystalline.

In some embodiments, the crystalline form of the3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamidehydrochloric acid salt has an XRPD profile substantially as shown inFIG. 4.

In some embodiments, the crystalline form of the3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamidehydrochloric acid salt has at least one, at least two, at least three,at least four, or at least five XRPD peaks, in terms of 2-theta,selected from about 9.9°, about 13.4°, about 14.1°, about 15.8°, about16.1°, about 16.2°, about 17.4°, about 18.0°, about 21.7°, about 22.0°,about 22.4°, about 23.4°, about 24.5°, about 25.3°, about 26.4°, about26.8°, and about 27.9°.

In some embodiments, the crystalline form of the3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamidehydrochloric acid salt has at least one, at least two, at least three,at least four, or at least five XRPD peaks, in terms of 2-theta,selected from about 9.9°, about 13.4°, about 14.1°, about 15.8°, about16.1°, about 16.2°, about 17.4°, about 18.0°, about 21.7°, about 22.0°,about 26.8°, and about 27.9°.

In some embodiments, the crystalline form of the3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamidehydrochloric acid salt is characterized by a DSC thermogram having anendothermic peak at about 233.4° C.

In some embodiments, the crystalline form of the3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamidehydrochloric acid salt is characterized by a thermographic analysis(TGA) substantially as shown in FIG. 6.

In some embodiments, the3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamidecan be isolated as a benzenesulfonic acid salt, which can becrystalline.

In some embodiments, the crystalline form of the3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamidebenzenesulfonic acid salt has an XRPD profile substantially as shown inFIG. 7.

In some embodiments, the crystalline form of the3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamidebenzenesulfonic acid salt has at least one, at least two, at leastthree, at least four, or at least five XRPD peaks, in terms of 2-theta,selected from about 14.8°, about 15.8°, about 16.5°, about 16.7°, about17.1°, about 18.6°, about 18.9°, about 19.2°, about 19.8°, about 22.2°,about 22.8°, about 23.6°, about 24.5°, about 24.9°, and about 25.9°.

In some embodiments, the crystalline form of the3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamidebenzenesulfonic acid salt is characterized by a DSC thermogram having anendothermic peak at about 213.8° C.

In some embodiments, the crystalline form of the3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamidebenzenesulfonic acid salt is characterized by a thermographic analysis(TGA) substantially as shown in FIG. 9.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. The substituents are independently selected, andsubstitution may be at any chemically accessible position. As usedherein, the term “substituted” means that a hydrogen atom is removed andreplaced by a substituent. A single divalent substituent, e.g., oxo, canreplace two hydrogen atoms. It is to be understood that substitution ata given atom is limited by valency.

Throughout the definitions, the term “C_(n-m)” indicates a range whichincludes the endpoints, wherein n and m are integers and indicate thenumber of carbons. Examples include C₁₋₄, C₁₋₆, and the like.

As used herein, the term “C_(n-m)alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. Examplesof alkyl moieties include, but are not limited to, chemical groups suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl,sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl. 3-pentyl,n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, thealkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms,from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. Examplealkenyl groups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments,the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_(n-m) alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term “C_(n-m)alkylene”, employed alone or incombination with other terms, refers to a divalent alkyl linking grouphaving n to m carbons. Examples of alkylene groups include, but are notlimited to, ethan-1,1-diyl, ethan-1,2-diyl, propan-1,1,-diyl,propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl,butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like. In someembodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to6, 1 to 4, or 1 to 2 carbon atoms.

As used herein, the term “C_(n-m)alkoxy”, employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has n to m carbons. Example alkoxy groupsinclude, but are not limited to, methoxy, ethoxy, propoxy (e.g.,n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

As used herein, the term “C_(n-m)alkylamino” refers to a group offormula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms. Examples of alkylamino groups include, but are not limited to,N-methylamino, N-ethylamino, N-propylamino (e.g., N-(n-propyl)amino andN-isopropylamino), N-butylamino (e.g., N-(n-butyl)amino andN-(tert-butyl)amino), and the like.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to an aromatic hydrocarbon group, which may bemonocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term“C_(n-m)aryl” refers to an aryl group having from n to m ring carbonatoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl,phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, arylgroups have from 6 to 10 carbon atoms. In some embodiments, the arylgroup is phenyl or naphthyl.

As used herein, the term “di(C_(n-m)-alkyl)amino” refers to a group offormula —N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, ahalo is F, Cl, or Br.

As used herein, “C_(n-m)haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. An example haloalkoxy group isOCF₃. In some embodiments, the haloalkoxy group is fluorinated only. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m)haloalkyl”, employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and/or alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups,spirocycles, and bridged rings. Ring-forming carbon atoms of acycloalkyl group can be optionally substituted by oxo or sulfido (e.g.,C(O) or C(S)). Also included in the definition of cycloalkyl aremoieties that have one or more aromatic rings fused (i.e., having a bondin common with) to the cycloalkyl ring, for example, benzo or thienylderivatives of cyclopentane, cyclohexane, and the like. A cycloalkylgroup containing a fused aromatic ring can be attached through anyring-forming atom including a ring-forming atom of the fused aromaticring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-formingcarbons (C₃₋₁₀). In some embodiments, the cycloalkyl is a C3-Mmonocyclic or bicyclic cyclocalkyl. In some embodiments, the cycloalkylis a C₃₋₇ monocyclic cyclocalkyl. In some embodiments, the cycloalkyl isa C₄₋₁₀ spirocycle or bridged cycloalkyl. Example cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbomyl, norpinyl, norcamyl, cubane, adamantane, bicyclo[1.1.1]pentyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl,bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, and the like. In someembodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl.

As used herein, “heteroaryl” refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen, and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3, or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having1, 2, 3 or 4 heteroatom ring members independently selected fromnitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with aring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ringatoms are independently selected from N, O, and S. Exemplaryfive-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl,thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroarylring is a heteroaryl with a ring having six ring atoms wherein one ormore (e.g., 1, 2, or 3) ring atoms are independently selected from N, O,and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl,pyrimidinyl, triazinyl and pyridazinyl.

As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic orpolycyclic heterocycles having one or more ring-forming heteroatomsselected from O, N, or S. Included in heterocycloalkyl are monocyclic4-14-membered heterocycloalkyl groups. Heterocycloalkyl groups can alsoinclude spirocycles and bridged rings, e.g., a 5-8 membered bridgedheterocycloalkyl ring optionally substituted with 0 to 2 additionalheteroatoms independently selected from nitrogen, oxygen and sulfur.Example heterocycloalkyl groups include pyrrolidin-2-one,1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl,morpholine, thiomorpholino, piperazinyl, tetrahydrofuranyl,tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl,isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, azepanyl, benzazapene, azabicyclo[3.1.0]hexanyl,diazabicyclo[3.1.0]hexanyl, oxabicyclo[2.1.1]hexanyl,azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl,azabicyclo[3.1.1]heptanyl, diazabicyclo[3.1.1]heptanyl,azabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]octanyl,oxabicyclo[2.2.2]octanyl, azabicyclo[2.2.2]octanyl, azaadamantanyl,diazaadamantanyl, oxa-adamantanyl, azaspiro[3.3]heptanyl,diazaspiro[3.3]heptanyl, oxa-azaspiro[3.3]heptanyl,azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl, oxa-azaspiro[3.4]octanyl,azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl, azaspiro[4.4]nonanyl,diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl, azaspiro[4.5]decanyl,diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl,oxa-diazaspiro[4.4]nonanyl and the like. Ring-forming carbon atoms andheteroatoms of a heterocycloalkyl group can be optionally substituted byoxo or sulfido (e.g., C(O), S(O), C(S), or S(O)₂, etc.). Theheterocycloalkyl group can be attached through a ring-forming carbonatom or a ring-forming heteroatom. In some embodiments, theheterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 double bonds.Also included in the definition of heterocycloalkyl are moieties thathave one or more aromatic rings fused (i.e., having a bond in commonwith) to the cycloalkyl ring, for example, benzo or thienyl derivativesof piperidine, morpholine, azepine, etc. A heterocycloalkyl groupcontaining a fused aromatic ring can be attached through anyring-forming atom including a ring-forming atom of the fused aromaticring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6membered heterocycloalkyl having 1 or 2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur and having one or moreoxidized ring members. In some embodiments, the heterocycloalkyl is amonocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or4 heteroatoms independently selected from nitrogen, oxygen, or sulfurand having one or more oxidized ring members.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas a pyridin-3-yl ringis attached at the 3-position.

As used herein, the term “oxo” refers to an oxygen atom (i.e., ═O) as adivalent substituent, forming a carbonyl group when attached to a carbon(e.g., C═O), or attached to a nitrogen or sulfur heteroatom forming anitroso, sulfinyl or sulfonyl group.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and tram geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms. In someembodiments, the compound has the (R)-configuration. In someembodiments, the compound has the (S)-configuration.

Formulas (I)-(XII) herein include stereoisomers of the compounds. Insome embodiments, the carbon atom to which R¹ is attached is in the(R)-configuration. In some embodiments, the carbon atom to which R¹ isattached is in the (S)-configuration.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallizaion using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such as(3-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds provided herein also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.hydrates and solvates) or can be isolated.

In some embodiments, preparation of compounds can involve the additionof acids or bases to affect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

Example acids can be inorganic or organic acids and include, but are notlimited to, strong and weak acids. Some example acids includehydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,p-toluenesulfonic acid, 4-nitrobenzoic acid, methanesulfonic acid,benzenesulfonic acid, trifluoroacetic acid, and nitric acid. Some weakacids include, but are not limited to acetic acid, propionic acid,butanoic acid, benzoic acid, tartaric acid, pentanoic acid, hexanoicacid, heptanoic acid, octanoic acid, nonanoic acid, and decanoic acid.

Example bases include lithium hydroxide, sodium hydroxide, potassiumhydroxide, lithium carbonate, sodium carbonate, potassium carbonate, andsodium bicarbonate. Some example strong bases include, but are notlimited to, hydroxide, alkoxides, metal amides, metal hydrides, metaldialkylamides and arylamines, wherein; alkoxides include lithium, sodiumand potassium salts of methyl, ethyl and t-butyl oxides; metal amidesinclude sodium amide, potassium amide and lithium amide; metal hydridesinclude sodium hydride, potassium hydride and lithium hydride; and metaldialkylamides include lithium, sodium, and potassium salts of methyl,ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, trimethylsilyl andcyclohexyl substituted amides.

In some embodiments, the compounds provided herein, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds providedherein. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds provided herein, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present application also includes pharmaceutically acceptable saltsof the compounds described herein. The present invention also includespharmaceutically acceptable salts of the compounds described herein. Asused herein, “pharmaceutically acceptable salts” refers to derivativesof the disclosed compounds wherein the parent compound is modified byconverting an existing acid or base moiety to its salt form. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids; and thelike. The pharmaceutically acceptable salts of the present inventioninclude the conventional non-toxic salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol, or butanol) or acetonitrile (ACN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal ofPharmaceutical Science, 66, 2 (1977), each of which is incorporatedherein by reference in its entirety.

Synthesis

As will be appreciated, the compounds provided herein, including saltsand stereoisomers thereof, can be prepared using known organic synthesistechniques and can be synthesized according to any of numerous possiblesynthetic routes.

Compounds of Formula (I) can be prepared from optionally protected(e.g., P=acetyl) bicycles 1-1 where Y¹ is halogen (e.g., Cl, Br, or I)or pseudohalogen (e.g., OTf or OMs) as shown in Scheme I. Bicycle 1-1can be coupled with 1-2, where M¹ is a boronic acid, boronate ester,potassium trifluoroborate, or an appropriately substituted metal, suchas Sn(Bu)₃ or Zn, under standard Suzuki conditions (e.g., in thepresence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(O) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complexwith dichloromethane and a base (e.g., a carbonate base)) or standardStille conditions (e.g., in the presence of a palladium(O) catalyst,such as tetrakis(triphenylphosphine)palladium(O)) or standard Negishiconditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(O) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to givecompound 1-3. After coupling, optionally chosen protecting groups can beremoved under conditions suitable for their removal that are alsocompatible with the functionality present in 1-3 (e.g., exposure toaqueous HCl) to afford the resulting compounds of Formula (I).

Alternatively, the Y¹ group can be converted to an appropriatesubstituted metal 1-4 (e.g., M² is B(OH)₂, Bpin, BF₃K, Sn(Bu)₃, or Zn)and then coupled to 1-5 where Y² is halogen (e.g., Cl, Br, or I) orpseudohalogen (e.g., OTf or OMs) under standard Suzuki conditions (e.g.,in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(O) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complexwith dichloromethane and a base (e.g., a carbonate base)) or standardStille conditions (e.g., in the presence of a palladium(O) catalyst,such as tetrakis(triphenylphosphine)palladium(O)) or standard Negishiconditions (e.g., in the presence of a palladium(O) catalyst, such astetrakis(triphenylphosphine)palladium(O) or[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium (II)) to giveto give compound 1-3. After coupling, optionally chosen protectinggroups can be removed under conditions suitable for their removal thatare also compatible with the functionality present in 1-3 (e.g.,exposure to aqueous HCl) to afford the resulting compounds of Formula(I).

Intermediates for making compounds of the invention can be prepared asshown in Scheme II. For example, sulfonyl halide 2-1, where Y³ is ahalogen (e.g., Cl or F), can be coupled with an amine 2-2 by variousmethods (e.g. treatment with an appropriate base such as pyridine ortrimethylamine and optionally with a catalyst such as4-dimethylaminopyridine). The Y² halo (e.g., Cl, Br, or I) or pseudohalogroup (e.g., OTf or OMs) of sulfonamide 2-3 can be converted to anappropriate substituted metal 2-4 (e.g., M² is B(OH)₂, Bpin, BF₃K,Sn(Bu)₃, or Zn) under standard conditions (e.g., in the presence of adiboron reagent such as bis(pinacolato)diboron, a palladium catalyst,such as dichloro[bis(triphenylphosphoranyl)]palladium orbis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane, and a base, such as potassium acetate). Compounds ofthe invention can be synthesized from intermediates 2-4 using themethods described in Scheme I.

Intermediates for making compounds of the invention can be prepared asshown in Scheme III. For example, an amine 3-1 can be coupled with asulfonyl halide 3-2, where Y⁴ is a halogen (e.g., Cl or F), by variousmethods (e.g. treatment with an appropriate base such as pyridine). TheY² halo (e.g., Cl, Br, or I) or pseudohalo group (e.g., OTf or OMs) ofsulfonamide 3-3 can be converted to an appropriate substituted metal 3-4(e.g., M² is B(OH)₂, Bpin, BF₃K, Sn(Bu)₃, or Zn) under standardconditions (e.g., in the presence of a diboron reagent such asbis(pinacolato)diboron, a palladium catalyst, such asdichloro[bis(triphenylphosphoranyl)]palladium orbis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane, and a base, such as potassium acetate). Compounds ofthe invention can be synthesized from intermediates 3-4 using themethods described in Scheme I.

Intermediates for making compounds of the invention can be prepared asshown in Scheme IV. For example, an aryl halide 4-1 can be converted toorganometallic reagent 4-2 where M³ is a metal (e.g., MgY^(a) whereY^(a) is a halide) under standard conditions (e.g., in the presence ofmagnesium and optionally an additive such as 1,2-dibromoethane orlithium chloride). The resulting organometallic reagent 4-2 can beconverted to the sulfinate 4-3 under standard conditions (e.g.,quenching with sulfur dioxide or 1,4-diazabicyclo[2.2.2]octanebis(sulfur dioxide) adduct) and then alkylated with reagent 4-4 where Y⁹is a halo group (e.g., Cl, Br, or I) or other leaving group (e.g., OMsor OTs) to give the sulfone 4-5. Halogenation with suitable reagents,such as Y-chlorosuccinimide, N-bromosuccinimide, Br₂, orN-iodosuccinimide can give halide 4-6 where Y² is a halo group (e.g.,Cl, Br, or I). The Y² halo can be converted to an appropriatesubstituted metal (e.g., M² is B(OH)₂, Bpin, BF₃K, Sn(Bu)₃, or Zn) understandard conditions (e.g., in the presence of a diboron reagent such asbis(pinacolato)diboron, a palladium catalyst, such asdichloro[bis(triphenylphosphoranyl)]palladium orbis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane, and a base, such as potassium acetate) to give 4-7.

Alternatively, an aryl halide 4-1 can be directly converted to thesulfonate 4-3 under standard metal-catalyzed conditions (e.g., in thepresence of a sulfur dioxide donor, such as potassium metabisulfite, apalladium catalyst such as palladium acetate, ligands such astriphenylphosphine and 1,10-phenathroline, and a base (e.g., sodiumformate)) and then alkylated with reagent 4-4 where Y⁹ is a halo group(e.g., Cl, Br, or I) or other leaving group (e.g., OMs or OTs) to givethe sulfone 4-5. The sulfone 4-5 can be halogenated and then metalatedto give 4-7. Compounds of the invention can be synthesized fromintermediates 4-4 using the methods described in Scheme I.

Compounds of Formula (I) can also be prepared as shown in Scheme V. Forexample, heteroaromatic amine 5-1, where Y⁴ is a halogen (e.g., Cl, Br,or I), can be reacted with alpha-halo carbonyl derivative 5-2 where Y⁵is a halogen (e.g., Cl or Br), to give heterocycle 5-3. The amino groupof 5-3 can be optionally protected with a suitable protecting group P,(e.g., acetyl), under standard conditions (e.g., in the presence ofacetyl chloride or acetic anhydride, a base (e.g., triethylamine), andoptionally a catalyst (e.g., 4-dimethylaminopyridine)) to give theprotected amine 5-4. Compound 5-4 can be halogenated with suitablereagents, such as N-chlorosuccinimide, N-bromosuccinimide, orN-iodosuccinimide, to give halide 5-5 where Y¹ is a halo group (e.g.,Cl, Br, or I). Halide 5-5 can be selectively coupled with 1-2, where M¹is a boronic acid, boronate ester, potassium trifluoroborate, or anappropriately substituted metal such as Sn(Bu)₃ or Zn, under standardSuzuki conditions (e.g., in the presence of a palladium catalyst, suchas tetrakis(triphenylphosphine)palladium(O) and a base (e.g., acarbonate base)) or standard Stille conditions (e.g., in the presence ofa palladium(O) catalyst, such astetrakis(triphenylphosphine)palladium(O)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(O) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to givecompound 5-6. Compound 5-6 can be coupled with 5-7, where M⁴ is aboronic acid, boronate ester, potassium trifluoroborate, or anappropriately substituted metal, such as Sn(Bu)₃ or Zn, under standardSuzuki conditions (e.g., in the presence of a palladium catalyst, suchas bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane orbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)and a base (e.g., a carbonate base or cesium fluoride)) or standardStille conditions (e.g., in the presence of a palladium(O) catalyst,such as tetrakis(triphenylphosphine)palladium(O)) or standard Negishiconditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(O) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to givecompound 5-8. The optionally chosen protecting group can be removedaccording to Scheme I to afford the resulting compounds of Formula (I).

Alternatively, halide 5-5 can be selectively coupled with 5-7, where M⁴is a boronic acid, boronate ester, potassium trifluoroborate, or anappropriately substituted metal such as Sn(Bu)₃ or Zn, under standardSuzuki conditions (e.g., in the presence of a palladium catalyst, suchas bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane orbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)and a base (e.g., a carbonate base or cesium fluoride)) or standardStille conditions (e.g., in the presence of a palladium(O) catalyst,such as tetrakis(triphenylphosphine)palladium(O)) or standard Negishiconditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(O) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to givecompound 5-9, which can be elaborated according to Scheme I to affordthe resulting compounds of Formula (I).

Compounds of Formula (I) can also be prepared as shown in Scheme VI. Forexample, hetereoaromatic amine 6-1, where Y⁴ and Y⁶ are halo groups, canbe reacted with alpha-halo carbonyl derivatives 5-2 where Y⁵ is ahalogen (e.g., Cl or Br), to give heterocycle 6-2. Halogenation ofheterocycle 6-2 with suitable reagents, such as N-chlorosuccinimide.N-bromosuccinimide, or N-iodosuccinimide can give halide 6-3 where Y¹ isa halo group (e.g., Cl, Br, or I). Nucleophilic aromatic substitution ofthe halide of 6-3 with amine 6-4 can provide halide 6-5. Halide 6-5 canbe selectively coupled with 1-2, where M¹ is a boronic acid, boronateester, potassium trifluoroborate, or an appropriately substituted metalsuch as Sn(Bu)₃ or Zn, under standard Suzuki conditions (e.g., in thepresence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(O) and a base (e.g., a carbonatebase)) or standard Stille conditions (e.g., in the presence of apalladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(O))or standard Negishi conditions (e.g., in the presence of a palladiumcatalyst, such as tetrakis(triphenylphosphine)palladium(O) or[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium (II)), to givecompound 6-6. Coupling of compound 6-6 with 6-7, where M⁴ is a boronicacid, boronate ester, potassium trifluoroborate, or an appropriatelysubstituted metal such as Sn(Bu)₃ or Zn, under standard Suzukiconditions (e.g., in the presence of a palladium catalyst, such asbis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane orbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)and a base (e.g., a carbonate base or cesium fluoride)) or standardStille conditions (e.g., in the presence of a palladium(O) catalyst,such as tetrakis(triphenylphosphine)palladium(O)) or standard Negishiconditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(O) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), canafford the resulting compounds of Formula (I).

Alternatively, selective coupling of halide 6-5 with 6-7, under standardSuzuki conditions (e.g., in the presence of a palladium catalyst, suchas bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane orbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)and a base (e.g., a carbonate base or cesium fluoride)) or standardStille conditions (e.g., in the presence of a palladium(O) catalyst,such as tetrakis(triphenylphosphine)palladium(O)) or standard Negishiconditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(O) or[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium (II)), canafford compound 6-8, which can be further reacted according to Scheme Ito afford the resulting compounds of Formula (I).

Compounds of Formula (I) can also be prepared as shown in Scheme VII.For example, hetereoaromatic amine 7-1, where Y⁶ is a halogen group, canbe reacted with alpha-halo carbonyl derivatives 5-2 where Y⁵ is ahalogen (e.g., Cl or Br), to give heterocycle 7-2. Halogenation ofheterocycle 7-2 with suitable reagents, such as N-chlorosuccinimide.N-bromosuccinimide, or N-iodosuccinimide, can give halide 7-3 where Y¹is a halo group (e.g., Cl, Br, or I). Nucleophilic aromatic substitutionof the halide 7-3 with amine 7-4 can provide halide 7-5. Halide 7-5 canbe further reacted according to Scheme I to afford the resultingcompounds of Formula (I).

Compounds of Formula (I) can also be prepared as shown in Scheme VIII.For example, hetereoaromatic amine 8-1, where Y⁷ is a halogen group, canbe reacted with alpha-halo carbonyl derivatives 5-2 where Y⁵ is ahalogen (e.g., Cl or Br), to give heterocycle 8-3. The amino group of8-3 can be optionally protected with a suitable protecting group P(e.g., acetyl), under standard conditions (e.g., in the presence ofacetyl chloride or acetic anhydride, a base (e.g., triethylamine), andoptionally a catalyst (e.g., 4-dimethylaminopyridine)) to give protectedamine 8-4. Compound 8-4 can be halogenated with suitable reagents, suchas N-chlorosuccinimide. N-bromosuccinimide, or N-iodosuccinimide, togive a halide 8-5 where Y¹ is a halo group (e.g., Cl, Br, or I). Halide8-5 can be selectively coupled with 1-2, where M¹ is a boronic acid,boronate ester, potassium trifluoroborate, or an appropriatelysubstituted metal such as Sn(Bu)₃ or Zn, under standard Suzukiconditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(O) and a base (e.g., a carbonatebase)) or standard Stille conditions (e.g., in the presence of apalladium(O) catalyst, such asbis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane) or standard Negishi conditions (e.g., in the presenceof a palladium catalyst, such astetrakis(triphenylphosphine)palladium(O) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to givecompound 8-6. Coupling of compound 8-6 with 8-7, where M⁵ is a boronicacid, boronate ester, potassium trifluoroborate, or an appropriatelysubstituted metal such as Sn(Bu)₃ or Zn, under standard Suzukiconditions (e.g., in the presence of a palladium catalyst, such asbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)and a base (e.g., cesium fluoride)) or standard Stille conditions (e.g.,in the presence of a palladium(O) catalyst, such astetrakis(triphenylphosphine)palladium(O)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(O) or[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium (II)), can givecompound 8-8. The optionally chosen protecting group can be removedaccording to Scheme I to afford the resulting compounds of Formula (I).

Alternatively, halide 8-5 can be selectively coupled with 8-7, where M⁴is a boronic acid, boronate ester, potassium trifluoroborate, or anappropriately substituted metal such as Sn(Bu)₃ or Zn, under standardSuzuki conditions (e.g., in the presence of a palladium catalyst, suchasbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)and a base (e.g cesium fluoride)) or standard Stille conditions (e.g.,in the presence of a palladium(O) catalyst, such astetrakis(triphenylphosphine)palladium(O)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(O) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to givecompound 8-9, which can be further reacted according to Scheme I toafford the resulting compounds of Formula (I).

Compounds of Formula (I) can also be prepared as shown in Scheme IX.Preparation of intermediate 9-7 from imidazole 9-1 can be achieved bymethods analogous to those described in International App. No. WO2014/011974, the disclosure of which is incorporated herein by referencein its entirety. Animation under standard conditions (e.g., in thepresence of an NH₂-transfer agent such as chloramine,0-(diphenylphosphinyl)hydroxylamine, or O-(4-nitrobenzoyl)hydroxylamineand a base such as sodium hydride, lithium hexamethyldisilazane, orpotassium tert-butoxide) and then condensation with an alkylchloroformate ClCO₂R¹³, where R¹³ is an alkyl group, under standardconditions (e.g. treatment with an appropriate base such as pyridine)can give compound 9-2. Cyclization of 9-2 in the presence of ammonia canprovide bicycle 9-3. The bicycle 9-3 can be halogenated with suitablereagents, such as N-chlorosuccinimide, A-bromosuccinimide, orN-iodosuccinimide, to give a halide 9-4 where Y¹ is a halo group (e.g.,Cl, Br, or I). Dehydrative halogenation (e.g., by treating with areagent such as POCl₃ or POBr₃) can afford compound 9-5, where Y⁴ and Y⁶are each halogens (e.g., Cl or Br). Nucleophilic aromatic substitutionof the halide of 9-5 with amine 9-6 can provide intermediate 9-7.

Intermediate 9-7 can be selectively coupled with 1-2, where M¹ is aboronic acid, boronate ester, potassium trifluoroborate, or anappropriately substituted metal such as Sn(Bu)₃ or Zn, under standardSuzuki conditions (e.g., in the presence of a palladium catalyst, suchas tetrakis(triphenylphosphine)palladium(O) and a base (e.g., acarbonate base)) or standard Stille conditions (e.g., in the presence ofa palladium(O) catalyst, such astetrakis(triphenylphosphine)palladium(O)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(O) or[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium (II)), to givecompound 9-8. Coupling of compound 9-8 with 9-9, where M⁴ is a boronicacid, boronate ester, potassium trifluoroborate, or an appropriatelysubstituted metal such as Sn(Bu)₃ or Zn, under standard Suzukiconditions (e.g., in the presence of a palladium catalyst, such asbis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane orbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)and a base (e.g., a carbonate base or cesium fluoride)) or standardStille conditions (e.g., in the presence of a palladium(O) catalyst,such as tetrakis(triphenylphosphine)palladium(O)) or standard Negishiconditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(O) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), canafford the resulting compounds of Formula (I).

Intermediates for making compounds of the invention can be prepared asshown in Scheme X. Bis-halogenation of heteroaromatic amine 10-1 withsuitable reagents, such as N-chlorosuccinimide, 7V-bromosuccinimide,Br₂, or N-iodosuccinimide can give halide 10-2 where Y⁴ and Y⁶ are eachhalogens (e.g., Cl, Br, or I). Nucleophilic aromatic substitution ofhalide 10-2 with amine 10-3 can provide compound 10-4. Compounds of theinvention can be synthesized from intermediates 10-2 and 10-4 using themethods described in Scheme VI and Scheme V, respectively.

Intermediates for making compounds of the invention can be prepared asshown in Scheme XI. Nucleophilic aromatic substitution of halide 11-1,where Y⁴ and Y⁸ are each halogens (e.g., Cl or Br), with ammonia canprovide heteroaromatic amine 11-2. Halogenation of heteroaromatic amine11-2 with suitable reagents, such as N-chlorosuccinimide.N-bromosuccinimide, Br₂, or N-iodosuccinimide, optionally in thepresence of a base, such sodium bicarbonate or sodium carbonate, cangive compound 11-3 where Y⁶ is a halo group (e.g., Cl, Br, or I).Nucleophilic aromatic substitution of compound 11-3 with amine 11-4 canprovide compound 11-5. Compounds of the invention can be synthesizedfrom intermediates 11-3 and 11-5 using the methods described in SchemeVI and Scheme V, respectively.

Intermediates for making compounds of the invention can be prepared asshown in Scheme XII. Nucleophilic aromatic substitution of halide 12-1,where Y⁸ is a halogen (e.g., Cl or Br), with ammonia can provideheteroaromatic amine 12-2. Halogenation of heteroaromatic amine 12-2with suitable reagents, such as N-chlorosuccinimide, N-bromosuccinimide,Br₂, or N-iodosuccinimide, optionally in the presence of a base, suchsodium bicarbonate or sodium carbonate, can give compound 12-3, where Y⁶is a halo group (e.g., Cl, Br, or I). Nucleophilic aromatic substitutionof compound 12-3 with amine 12-4 can provide compound 12-5. Compounds ofthe invention can be synthesized from intermediates 12-3 and 12-5 usingthe methods described in Scheme VI and Scheme V, respectively.

In addition to the synthetic route outlined in Scheme I (hereinafterreferred to as Method A), which uses intermediates 2-4 formed as shownin Scheme II, compounds of Formula (I) can also be prepared as shown inScheme X (Method B). In Method B, halide X-1 where Y¹ is a halogen(e.g., Cl, Br or I) can be coupled with X-2 where M¹ is a boronic acid,boronate ester, potassium trifluoroborate, or an appropriatelysubstituted metal such as Sn(Bu)₃ or Zn, under standard Suzukiconditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(O) and a base (e.g., a carbonatebase)) or standard Stille conditions (e.g., in the presence of apalladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(O))or standard Negishi conditions (e.g., in the presence of a palladiumcatalyst, such as tetrakis(triphenylphosphine)palladium(O) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to givecompound X-3. Intermediate X-3 can be treated with chlorosulfonic acidin a suitable solvent at a temperature ranging from 0° C. to 50° C. toafford sulfonyl chloride X-4. Sulfonyl chloride can be reacted with anamine X-5 in the presence of base (such as triethylamine or Hunig'sbase) to afford compounds of Formula (I).

Intermediates 1-1 (Scheme I) useful for preparing compounds of Formula(I) wherein X² is N and of varying substitution at R⁸ can be preparedvia the method shown in Scheme Y. Condensation of Y-1 with an amidine atelevated temperature (e.g., 80 to 95° C.) in a suitable solvent (e.g.,EtOH) affords bicyclic intermediate Y-2. Alternatively, Y-1 can betreated with a nitrile and acid (e.g., HCl) in a suitable solvent (e.g.,dioxane) at elevated temperature (e.g., 100 to 110° C.) to afford Y-2.In some cases of cyclization the use of nitriles requires that thereaction mixture is made basic in the second step to facilitatecyclization. Intermediate Y-2 can be halogenated with suitable reagents,such as N-chlorosuccinimide. N-bromosuccinimide, Br₂ orN-iodosuccinimide to afford halide Y-3 where Y¹ is a halo group (e.g.,Cl, Br, or I). Dehydrative halogenation (e.g., by treating with areagent such as POCl₃ or POBr₃) can afford compound Y-4 where Y⁶ is ahalogen (e.g., Cl or Br). Nucleophilic aromatic substitution of thehalide of Y-4 with ammonia (e.g., using aq. NH₄OH solution) can provideintermediates Y-5, useful for preparing compounds of Formula (I).Alternatively, intermediate Y-3 can be condensed with an amine R⁷NH₂(e.g., p-methoxybenzylamine) with a coupling reagent (e.g., BOP) to giveintermediate Y-6. Deprotection of Y-6 (e.g., using TFA) can give Y-5.

Alternatively, intermediates 1-1 (Scheme I) useful for preparingcompounds of Formula (I) wherein X² is N and of varying substitution atR⁸ can be prepared via the method shown in Scheme Y-B. Condensation ofY-7 with an amidine at elevated temperature (e.g., 80 to 95° C.) in asuitable solvent (e.g., EtOH) affords bicyclic intermediate Y-8.Alternatively, Y-7 can be treated with a nitrile and acid (e.g., HCl) ina suitable solvent (e.g., dioxane) at elevated temperature (e.g., 100 to110° C.) to afford Y-8. In some cases of cyclization the use of nitrilesrequires that the reaction mixture is made basic in the second step tofacilitate cyclization. Intermediate Y-8 can be halogenated withsuitable reagents, such as N-chlorosuccinimide. N-bromosuccinimide, Br₂or N-iodosuccinimide to afford intermediates Y-5, useful for preparingcompounds of Formula (I).

Substituents at R⁹ may be introduced following the procedure shown inScheme Z. Intermediate Z-1 can be halogenated with suitable reagents,such as N-chlorosuccinimide. N-bromosuccinimide, Br₂ orN-iodosuccinimide to afford halide Z-2 where Y⁹ is a halo group (e.g.,Cl, Br, or I). The Y⁹ halo group of Z-2 can be coupled to R⁹-M (Z-3)(e.g., M is B(OH)₂, Bpin, BF₃K, Sn(Bu)₃, Zn or Al) under standardconditions for Suzuki, Stille, Negishi and the like, in the presence ofa palladium catalyst, and where appropriate, a base, to afford compoundsof Formula (I).

Substituents at R⁴ may be introduced following the procedure outlined inScheme Q. Intermediate Q-1 can be selectively coupled with Q-2 bearing ahalogen substituent Y⁴ (e.g., C1) to afford intermediate Q-3. The Y⁴halo group of Q-3 can be coupled to R⁴-M (Q-4) (e.g., M is B(OH)₂, Bpin,BF₃K, Sn(Bu)₃, Zn or Al) under standard conditions for Suzuki, Stille,Negishi and the like, in the presence of a palladium catalyst and whereappropriate, a base, to afford compounds of Formula (I).

Where not commercially available, optionally protected (“PHN”) amines,such as YY-1 wherein X⁷ can be N, O, or C and optionally substitutedwith 0, 1 or 2 R^(b) groups; and m, n, p can independently be 0, 1, 2, 3or 4, required to prepare compounds of Formula (I) can be preparedfollowing the steps outlined in Scheme YY. Carboxylic acid YY-1 can beconverted to a primary amide YY-2 by activation using an alkylchloroformate (e.g., ethyl chloroformate) in the presence of a base(e.g., Hunig's base or triethylamine) followed by reaction with anammonia source (e.g., aq. NH₄OH solution) to afford primary amideintermediate YY-2. Alternative activating agents can be used in thistransformation (e.g., thionyl chloride, oxalyl chloride or peptidecoupling reagents such as DCC, or HATU). Primary amide YY-2 can beconverted to nitrile YY-3 using reagents for dehydration (e.g.,trichloroacetyl chloride, thionyl chloride, trifluoroacetic anhydride)in the presence of base (e.g., Hunig's base or triethylamine).

Where not commercially available, optionally protected (P) amines, suchas XX-1 wherein X⁷ can be N, O, or C and optionally substituted with 0,1 or 2 R^(b) groups; m, n, p can independently be 0, 1, 2, 3 or 4, and Rcan be alkyl (e.g., methyl, ethyl ester) or a leaving group formed byactivation with reagents (e.g., chloroformate), required to preparecompounds of Formula (I) can also be prepared following the stepsoutlined in Scheme XX. Ester XX-1 can be reacted with a nucleophile(e.g., a Grignard reagent or alkyllithium reagent) to afford alcoholXX-2 or reduced to afford XX-6. The carboxylic acid XX-3 can beconverted to heterocycles XX-4 by methods known to one skilled in theart. Alternatively, the carboxylic acid of XX-3 can be converted intocarboxylic amides, XX-5, by treatment with an amine in the presence of acoupling reagent and base. The carboxylic acid can also give rise toalcohol XX-6 via reduction. Alcohol XX-6 can be used to affordfluorinated products such as XX-7 by deoxofluorination or oxidation toXX-8, followed by deoxofluorination to afford XX-9. Derivatives such asXX-10 and XX-11 can be prepared by activation of the alcohol todisplacement by conversion to a leaving group (e.g., Cl, Br, I, OMs orOTs) and carrying out the displacement with cyanide, amines orheterocycles. Alternatively, optionally protected amines XX-11 can beprepared by reductive animation of aldehyde XX-8. Amines such as XX-12can be functionalized via reductive amination, acylation and otherreactions known to one skilled in the art, to afford intermediates oftype XX-13 which are useful for preparing compounds of Formula (I).Depending on which compound of Formula (I) being prepared the R groupspending from XX-1 to XX-13 can be any selected from any of theappropriate R groups as described in this disclosure. Scheme XX.

Where desired, any of the amines from Scheme YY or Scheme XX can be usedto prepare secondary amines by alkylation before removal of theprotecting group as shown in Scheme XX-B. Suitably protected aminesXX-B-1 can be treated with base (e.g., NaH, K₂CO₃) and an alkylatingagent R′-LG wherein LG is a leaving group (e.g., Cl, Br, I, OMs or OTs),to afford intermediate XX-B-2. Deprotection furnishes secondary aminesXX-B-3 which are useful for preparing compounds of Formula (I).

The reactions for preparing compounds described herein can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,(e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature). A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

The expressions, “ambient temperature” and “room temperature” or “rt” asused herein, are understood in the art, and refer generally to atemperature, e.g. a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Preparation of compounds described herein can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., Wiley &Sons, Inc., New York (1999).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) and normal phase silicachromatography.

Methods of Use

The compounds, salts or stereoisomers thereof described herein inhibitactivity of PI3Kγ kinase. Accordingly, the compounds, salts orstereoisomers described herein can be used in methods of inhibitingPI3Kγ kinase by contacting the kinase with any one or more of thecompounds, salts, or compositions described herein. In some embodiments,the compounds or salts can be used in methods of inhibiting activity ofPI3Kγ in an individual/patient in need of the inhibition byadministering an effective amount of a compound or salt of describedherein. In some embodiments, modulating is inhibiting. In someembodiments, the contacting is in vivo. In some embodiments, thecontacting is ex vivo. Advantageously, the compounds as described hereindemonstrate better efficacy and favorable safety and toxicity profilesin animal studies.

In some embodiments, the PI3Kγ includes a mutation. A mutation can be areplacement of one amino acid for another, or a deletion of one or moreamino acids. In such embodiments, the mutation can be present in thekinase domain of the PI3Kγ.

In some embodiments, the compound or salt further inhibits PI3Kδ.

The compounds or salts described herein can be selective. By “selective”is meant that the compound binds to or inhibits PI3Kγ with greateraffinity or potency, respectively, compared to at least one otherkinase. In some embodiments, the compounds of the invention areselective inhibitors of PI3Kγ over PI3Kδ, PI3Kα, and PI3Kβ. In someembodiments, the compounds of the invention are selective inhibitors ofPI3Kγ over PI3Kα and PI3Kβ. In some embodiments, selectivity can be atleast about 2-fold, 3-fold, 5-fold, 10-fold, at or 20-fold over PI3Kδ asmeasured by the assays described herein. In some embodiments,selectivity can be tested at the K_(m) ATP concentration of each enzyme.In some embodiments, the selectivity of compounds of the invention canbe determined by cellular assays associated with particular PI3K kinaseactivity.

Another aspect of the present invention pertains to methods of treatinga kinase PI3Kγ-associated disease or disorder in an individual (e.g.,patient) by administering to the individual in need of such treatment atherapeutically effective amount or dose of one or more compounds of thepresent invention or a pharmaceutical composition thereof. API3Kγ-associated disease or disorder can include any disease, disorderor condition that is directly or indirectly linked to expression oractivity of the PI3Kγ, including overexpression and/or abnormal activitylevels.

In some embodiments, the disease or disorder is an autoimmune disease ordisorder, cancer, cardiovascular disease, or neurodegenerative disease.

In some embodiments, the disease or disorder is lung cancer (e.g.,non-small cell lung cancer), melanoma, pancreatic cancer, breast cancer,prostate cancer, liver cancer, color cancer, endometrial cancer, bladdercancer, skin cancer, cancer of the uterus, renal cancer, gastric cancer,or sarcoma. In some embodiments, the sarcoma is Askin's tumor, sarcomabotryoides, chondrosarcoma, Ewing's sarcoma, malignanthemangioendothelioma, malignant schwannoma, osteosarcoma, alveolar softpart sarcoma, angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcomaprotuberans, desmoid tumor, desmoplastic small round cell tumor,epithelioid sarcoma, extraskeletal chondrosarcoma, extraskeletalosteosarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST),hemangiopericytoma, hemangiosarcoma, Kaposi's sarcoma, leiomyosarcoma,liposarcoma, lymphangiosarcoma, lymphosarcoma, malignant peripheralnerve sheath tumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma,synovial sarcoma, or undifferentiated pleomorphic sarcoma.

In some embodiments, the disease or disorder is acute myeloid leukemia(e.g., acute monocytic leukemia), small lymphocyctic lymphoma, chroniclymphocytic leukemia (CEL), chronic myelogenous leukemia (CML), multiplemyeloma, T-cell actute lymphoblasic leukemia (T-ALL), cutaneous T-celllymphoma, large granular lymphocytic leukemia, mature (peripheral)t-cell neoplasm (PTCL), anaplastic large cell lymphoma (ALCL), orlymphoblastic lymphoma. In some embodiments, the mature (peripheral)t-cell neoplasm (PTCL) is T-cell prolymphocytic leukemia, T-cellgranular lymphocytic leukemia, aggressive NK-cell leukemia, mycosisfimgoides/Sezary syndrome, naplastic large cell lymphoma (T-cell type),enteropathy type T-cell lymphoma, adult T-cell leukemia/lymphoma, orangioimmunoblastic T-cell lymphoma. In some embodiments, the anaplasticlarge cell lymphoma (ALCL) is systemic ALCL or primary cutaneous ALCL.

In some embodiments, the disease or disorder is Burkitt's lymphoma,acute myeloblastic leukemia, chronic myeloid leukemia, non-Hodgkin'slymphoma, Hodgkin's lymphoma, hairy cell leukemia, Mantle cell lymphoma,small lymphocytic lymphoma, follicular lymphoma, xenoderoma pigmentosum,keratoctanthoma, lymphoplasmacytic lymphoma, extranodal marginal zonelymphoma, Waldenstrom's macroglobulinemia, prolymphocytic leukemia,acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphatictissue (MALT) lymphoma, mediastinal (thymic) large B-cell lymphoma,lymphomatoid granulomatosis, splenic marginal zone lymphoma, primaryeffusion lymphoma, intravascular large B-cell lymphoma, plasma cellleukemia, extramedullary plasmacytoma, smouldering myeloma (akaasymptomatic myeloma), monoclonal gammopathy of undeterminedsignificance (MGUS), or diffuse large B cell lymphoma.

In some embodiments, the disease or disorder is Burkitf s lymphoma,acute myeloblastic leukemia, chronic myeloid leukemia, non-Hodgkin'slymphoma, Hodgkin's lymphoma, hairy cell leukemia, Mantle cell lymphoma,small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacyticlymphoma, extranodal marginal zone lymphoma, Waldenstrom'smacroglobulinemia, prolymphocytic leukemia, acute lymphoblasticleukemia, myelofibrosis, mucosa-associated lymphatic tissue (MALT)lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoidgranulomatosis, splenic marginal zone lymphoma, primary effusionlymphoma, intravascular large B-cell lymphoma, plasma cell leukemia,extramedullary plasmacytoma, smouldering myeloma (aka asymptomaticmyeloma), monoclonal gammopathy of undetermined significance (MGUS), ordiffuse large B cell lymphoma.

In some embodiments, the non-Hodgkin's lymphoma (NHL) is relapsed NHL,refractory NHL, recucurrent follicular NHL, indolent NHL (iNHL), oraggressive NHL (aNHL).

In some embodiments, the diffuse large B cell lymphoma is activatedB-cell like (ABC) diffuse large B cell lymphoma, or germinal center Bcell (GCB) diffuse large B cell lymphoma.

In some embodiments, the Burkitt's lymphoma is endemic Burkitf slymphoma, sporadic Burkitf s lymphoma, or Burkitf s-like lymphoma

In some embodiments, the disease or disorder is rheumatoid arthritis,multiple sclerosis, systemic lupus erythematous, asthma, allergy (e.g.,allergic rhinitis), pancreatitis, psoriasis, anaphylaxis,glomerulonephritis, inflammatory bowel disease (e.g., Crohn's diseaseand ulcerative colitis), thrombosis, meningitis, encephalitis, diabeticretinopathy, benign prostatic hypertrophy, myasthenia gravis, Sjögren'ssyndrome, osteoarthritis, restenosis, or atherosclerosis.

In some embodiments, the disease or disorder is heart hypertropy,cardiac myocyte dysfunction, acute coronary syndrome, chronicobstructive pulmonary disease (COPD), chronic bronchitis, elevated bloodpressure, ischemia, ischemia-reperfusion, vasoconstriction, anemia(e.g., hemolytic anemia, aplastic anemia, or pure red cell anemia),bacterial infection, viral infection, graft rejection, kidney disease,anaphylactic shock fibrosis, skeletal muscle atrophy, skeletal musclehypertrophy, angiogenesis, sepsis, graft-versus-host disease, allogeneicor xenogeneic transplantation, glomerulosclerosis, progressive renalfibrosis, idiopathic thrombocytopenic purpura (ITP), autoimmunehemolytic anemia, vasculitis, lupus nephritis, pemphigus, or membranousnephropathy.

In some embodiments, disease or disorder is heart hypertropy, cardiacmyocyte dysfunction, chronic obstructive pulmonary disease (COPD),elevated blood pressure, ischemia, ischemia-reperfusion,vasoconstriction, anemia (e.g., hemolytic anemia, aplastic anemia, orpure red cell anemia), bacterial infection, viral infection, graftrejection, kidney disease, anaphylactic shock fibrosis, skeletal muscleatrophy, skeletal muscle hypertrophy, angiogenesis, sepsis, graftrejection, glomerulosclerosis, progressive renal fibrosis, idiopathicthrombocytopenic purpura (ITP), autoimmune hemolytic anemia, vasculitis,systemic lupus erythematosus, lupus nephritis, pemphigus, or membranousnephropathy. In some embodiments, the disease or disorder is Alzheimer'sdisease, central nervous system trauma, or stroke.

In some embodiments, the idiopathic thrombocytopenic purpura (ITP) isrelapsed ITP or refractory ITP.

In some embodiments, the vasculitis is Behçet's disease, Cogan'ssyndrome, giant cell arteritis, polymyalgia rheumatica (PMR), Takayasu'sarteritis, Buerger's disease (thromboangiitis obliterans), centralnervous system vasculitis, Kawasaki disease, polyarteritis nodosa,Churg-Strauss syndrome, mixed cryoglobulinemia vasculitis (essential orhepatitis C virus (HCV)-induced), Henoch-Schonlein purpura (HSP),hypersensitivity vasculitis, microscopic polyangiitis, Wegener'sgranulomatosis, or anti-neutrophil cytoplasm antibody associated (ANCA)systemic vasculitis (AASV).

The present invention further provides a compound described herein, or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

The present invention further provides use of a compound describedherein, or a pharmaceutically acceptable salt thereof, for thepreparation of a medicament for use in any of the methods describedherein.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a PI3K with a compound of the invention includesthe administration of a compound of the present invention to anindividual or patient, such as a human, having a PI3K, as well as, forexample, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the PI3K.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician.

As used herein, the term “treating” or “treatment” can refer to one ormore of (1) inhibiting the disease; for example, inhibiting a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., arresting further development of the pathology and/orsymptomatology); and (2) ameliorating the disease; for example,ameliorating a disease, condition or disorder in an individual who isexperiencing or displaying the pathology or symptomatology of thedisease, condition or disorder (i.e., reversing the pathology and/orsymptomatology) such as decreasing the severity of disease.

Combination Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Targeting more than one signaling pathway (or more than onebiological molecule involved in a given signaling pathway) may reducethe likelihood of drug-resistance arising in a cell population, and/orreduce the toxicity of treatment.

The compounds of the present disclosure can be used in combination withone or more other enzyme/protein/receptor inhibitors or one or moretherapies for the treatment of diseases, such as cancer. Examples ofdiseases and indications treatable with combination therapies includethose as described herein. Examples of cancers include solid tumors andliquid tumors, such as blood cancers.

One or more additional pharmaceutical agents such as, for example,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors,chemokine receptor inhibitors, and phosphatase inhibitors, as well asBcr-Abl, Flt-3, EGER, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAFand FAR kinase inhibitors such as, for example, those described in WO2006/056399. Other agents such as therapeutic antibodies can be used incombination with the compounds of the present invention for treatment ofPI3K-associated diseases, disorders or conditions. The one or moreadditional pharmaceutical agents can be administered to a patientsimultaneously or sequentially.

For example, the compounds as disclosed herein can be combined with oneor more inhibitors of the following kinases for the treatment of cancerand other diseases or disorders described herein: Akt1, Akt2, Akt3,TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK,MAPK, mTOR, EGER, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR,CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4,c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphAl, EphA2,EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK,ABE, ALK and B-Raf. Non-limiting examples of inhibitors that can becombined with the compounds of the present disclosure for treatment ofcancer and other diseases and disorders described herein include an EGERinhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., INCB54828, INCB62079 andINCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g., ruxolitinib,baricitinib or INCB39110), an IDO inhibitor (e.g., epacadostat, NLG919,or BMS-986205), an ESDI inhibitor (e.g., INCB59872 and INCB60003), a TDOinhibitor, a PI3K-delta inhibitor (e.g., INCB50797 and INCB50465), a Piminhibitor, a CSFIR inhibitor, a TAM receptor tyrosine kinases (Tyro-3,Axl, and Mer), a histone deacetylase inhibitor (HDAC) such as an HDAC8inhibitor, an angiogenesis inhibitor, an interleukin receptor inhibitor,bromo and extra terminal family members inhibitors (for example,bromodomain inhibitors or BET inhibitors such as INCB54329 andINCB57643) and an adenosine receptor antagonist or combinations thereof.

In some embodiments, the compound or salt described herein isadministered with a PI3Kδ inhibitor. In some embodiments, the compoundor salt described herein is administered with a JAK inhibitor. In someembodiments, the compound or salt described herein is administered witha JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In someembodiments, the compound or salt described herein is administered witha JAK1 inhibitor. In some embodiments, the compound or salt describedherein is administered with a JAK1 inhibitor, which is selective overJAK2.

Example antibodies for use in combination therapy include but are notlimited to Trastuzumab (e.g. anti-HER2), Ranibizumab (e.g. anti-VEGF-A),Bevacizumab (trade name Avastin, e.g. anti-VEGF, Panitumumab (e.g.anti-EGFR), Cetuximab (e.g. anti-EGFR), Rituxan (anti-CD20) andantibodies directed to c-MET.

One or more of the following agents may be used in combination with thecompounds of the present invention and are presented as a non limitinglist: a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol,etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel,epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide,cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa,Tarceva, antibodies to EGFR, Gleevec™, intron, ara-C, adriamycin,cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide,Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin,EFOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin,Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17.alpha.-Ethinylestradiol, Diethylstilbestrol, Testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Feuprolide, Flutamide,Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Fevamisole, Navelbene,Anastrazole, Fetrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin,Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Fiposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Ferozole, Fulvestrant, Exemestane,Fulvestrant, Ifosfomide, Rituximab, C225, Campath, Clofarabine,cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine,Smll, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP,and MDF-101,731.

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumortargeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IF-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, adoptive T celltransfer, Toll receptor agonists, STING agonists, oncolytic virotherapyand immunomodulating small molecules, including thalidomide or JAK1/2inhibitor and the like. The compounds can be administered in combinationwith one or more anti-cancer drugs, such as a chemotherapeutics. Examplechemotherapeutics include any of: abarelix, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide,asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib,bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral,calusterone, capecitabine, carboplatin, carmustine, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib,daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane,docetaxel, doxorubicin, dromostanolone propionate, eculizumab,epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide,exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine,fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumabozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan,idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lomustine, meclorethamine, megestrolacetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycinC, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine,nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab,pegaspargase, pegfdgrastim, pemetrexed disodium, pentostatin,pipobroman, plicamycin, procarbazine, quinacrine, rasburicase,rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinibmaleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide,thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, uracil mustard, valrubicin, vinblastine, vincristine,vinorelbine, vorinostat and zoledronate.

Additional examples of chemotherapeutics include proteosome inhibitors(e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents suchas melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example steroids include corticosteroids such as dexamethasone orprednisone.

Example Bcr-Abl inhibitors include the compounds, and pharmaceuticallyacceptable salts thereof, of the genera and species disclosed in U.S.Pat. No. 5,521,184, WO 04/005281, and U.S. Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 03/037347, WO03/099771, and WO 04/046120.

Example suitable RAF inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 00/09495 and WO05/028444.

Example suitable FAK inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 04/080980, WO04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO 01/014402.

In some embodiments, the compounds of the invention can be used incombination with one or more other kinase inhibitors including imatinib,particularly for treating patients resistant to imatinib or other kinaseinhibitors.

In some embodiments, the compounds of the invention can be used incombination with a chemotherapeutic in the treatment of cancer, and mayimprove the treatment response as compared to the response to thechemotherapeutic agent alone, without exacerbation of its toxic effects.In some embodiments, the compounds of the invention can be used incombination with a chemotherapeutic provided herein. For example,additional pharmaceutical agents used in the treatment of multiplemyeloma, can include, without limitation, melphalan, melphalan plusprednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib).Further additional agents used in the treatment of multiple myelomainclude Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfdzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM). Additive or synergistic effects are desirableoutcomes of combining a PI3K inhibitor of the present invention with anadditional agent.

In some embodiments, PI3Kγ inhibitors provided herein can be used incombination with one or more immune checkpoint inhibitors for thetreatment of cancer as described herein. In one embodiment, thecombination with one or more immune checkpoint inhibitors as describedherein can be used for the treatment of melanoma. Compounds of thepresent disclosure can be used in combination with one or more immunecheckpoint inhibitors. Exemplary immune checkpoint inhibitors includeinhibitors against immune checkpoint molecules such as CD20, CD27, CD28,CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3Kgamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3,B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1 and PD-L2. In someembodiments, the immune checkpoint molecule is a stimulatory checkpointmolecule selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137. Insome embodiments, the immune checkpoint molecule is an inhibitorycheckpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO,KIR, LAG3, PD-1, TIM3, and VISTA. In some embodiments, the compounds ofthe invention provided herein can be used in combination with one ormore agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, orAMP-224. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibodyis pembrolizumab. In some embodiments, the anti-PD1 antibody isSHR-1210. Other anti-cancer agent(s) include antibody therapeutics suchas 4-IBB (e.g. urelumab, utomilumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228,BMS-986156, GWN323, or MEDI1873.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusionprotein. In some embodiments, the anti-OX40 antibody is MEDI0562,MOXR-0916, PF-04518600, GSK3174998, or BMS-986178. In some embodiments,the OX40L fusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor.

In some embodiments, the compounds of the invention can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO 1,TDO, or arginase. Examples of IDO 1 inhibitors include epacadostat andNGL919.

In some embodiments, the compounds of the invention can be used incombination with an inhibitor of JAK or PI3Kδ.

The agents can be combined with the present compound in a single orcontinuous dosage form, or the agents can be administered simultaneouslyor sequentially as separate dosage forms.

The compounds of the present disclosure can be used in combination withone or more other inhibitors or one or more therapies for the treatmentof infections. Examples of infections include viral infections,bacterial infections, fungus infections or parasite infections.

In some embodiments, a corticosteroid such as dexamethasone isadministered to a patient in combination with the compounds of theinvention where the dexamethasone is administered intermittently asopposed to continuously.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp100, MAGE antigens,Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to expressthe cytokine GM-CSF.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with a vaccination protocol forthe treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I) or any of the formulasas described herein, a compound as recited in any of the claims anddescribed herein, or salts thereof can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

In some further embodiments, combinations of the compounds of theinvention with other therapeutic agents can be administered to a patientprior to, during, and/or after a bone marrow transplant or stem celltransplant. The compounds of the present disclosure can be used incombination with bone marrow transplant for the treatment of a varietyof tumors of hematopoietic origin.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with vaccines, to stimulate theimmune response to pathogens, toxins, and self antigens. Examples ofpathogens for which this therapeutic approach may be particularlyuseful, include pathogens for which there is currently no effectivevaccine, or pathogens for which conventional vaccines are less thancompletely effective. These include, but are not limited to, HIV,Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania,Staphylococcus aureus, Pseudomonas aeruginosa.

Viruses causing infections treatable by methods of the presentdisclosure include, but are not limit to human papillomavirus,influenza, hepatitis A, B, C or D viruses, adenovirus, poxyirus, herpessimplex viruses, human cytomegalovirus, severe acute respiratorysyndrome virus, ebola virus, measles virus, herpes virus (e.g., VZV,HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses, echovirus, rhino virus, coxsackie virus, comovirus, respiratory syncytialvirus, mumpsvirus, rotavirus, measles virus, rubella virus, parvovirus,vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscumvirus, poliovirus, rabies virus, JC virus and arboviral encephalitisvirus.

Pathogenic bacteria causing infections treatable by methods of thedisclosure include, but are not limited to, chlamydia, rickettsialbacteria, mycobacteria, staphylococci, streptococci, pneumonococci,meningococci and conococci, klebsiella, proteus, serratia, pseudomonas,legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism,anthrax, plague, leptospirosis, and Lyme's disease bacteria.

Pathogenic fungi causing infections treatable by methods of thedisclosure include, but are not limited to, Candida (albicans, krusei,glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus(fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus),Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioidesbrasiliensis, Coccidioides immitis and Histoplasma capsulatum.Pathogenic parasites causing infections treatable by methods of thedisclosure include, but are not limited to, Entamoeba histolytica,Balantidium coli, Naegleria fowleri, Acanthamoeba sp., Giardia lambia,Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesiamicroti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,Toxoplasma gondi, and Nippostrongylus brasiliensis. Methods for the safeand effective administration of most of these chemotherapeutic agentsare known to those skilled in the art. In addition, their administrationis described in the standard literature. For example, the administrationof many of the chemotherapeutic agents is described in the “Physicians'Desk Reference” (PDR, e.g., 1996 edition, Medical Economics Company,Montvale, N.J.), the disclosure of which is incorporated herein byreference as if set forth in its entirety.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the invention or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196. Some examples of suitable excipients include lactose,dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calciumphosphate, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water,syrup, and methyl cellulose.

The formulations can additionally include: lubricating agents such astalc, magnesium stearate, and mineral oil; wetting agents; emulsifyingand suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), more usually about 100to about 500 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

In some embodiments, the compositions of the invention contain fromabout 5 to about 50 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 5 to about 10, about 10 to about 15, about 15 to about20, about 20 to about 25, about 25 to about 30, about 30 to about 35,about 35 to about 40, about to about 45, or about 45 to about 50 mg ofthe active ingredient.

In some embodiments, the compositions of the invention contain fromabout 50 to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 50 to about 100, about 100 to about 150, about 150 toabout 200, about 200 to about 250, about 250 to about 300, about 350 toabout 400, or about 450 to about 500 mg of the active ingredient.

In some embodiments, the compositions of the invention contain fromabout 500 to about 1000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 500 to about 550, about 550 to about 600, about 600 toabout 650, about 650 to about 700, about 700 to about 750, about 750 toabout 800, about 800 to about 850, about 850 to about 900, about 900 toabout 950, or about 950 to about 1000 mg of the active ingredient.

Similar dosages may be used of the compounds described herein in themethods and uses of the invention.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the invention. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the invention can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted herein.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe invention (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating PI3K in tissue samples,including human, and for identifying PI3K ligands by inhibition bindingof a labeled compound. Accordingly, the present invention includes PI3Kassays that contain such labeled compounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. For example, one or more hydrogenatoms in a compound of the present disclosure can be replaced bydeuterium atoms (e.g., one or more hydrogen atoms of a C₁₋₆alkyl groupof Formula (I) can be optionally substituted with deuterium atoms, suchas —CD₃ being substituted for —CH₃). The radionuclide that isincorporated in the instant radio-labeled compounds will depend on thespecific application of that radio-labeled compound. For example, for invitro PI3K labeling and competition assays, compounds that incorporate³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or will generally be most useful. Forradio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Bror ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

The present invention can further include synthetic methods forincorporating radio-isotopes into compounds of the invention. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind a PI3K by monitoring its concentrationvariation when contacting with the PI3K, through tracking of thelabeling. For example, a test compound (labeled) can be evaluated forits ability to reduce binding of another compound which is known to bindto a PI3K (i.e., standard compound). Accordingly, the ability of a testcompound to compete with the standard compound for binding to the PI3Kdirectly correlates to its binding affinity. Conversely, in some otherscreening assays, the standard compound is labeled and test compoundsare unlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of PI3K-associated diseases ordisorders, such as cancer, which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention. Such kits can furtherinclude, if desired, one or more of various conventional pharmaceuticalkit components, such as, for example, containers with one or morepharmaceutically acceptable carriers, additional containers, etc., aswill be readily apparent to those skilled in the art. Instructions,either as inserts or as labels, indicating quantities of the componentsto be administered, guidelines for administration, and/or guidelines formixing the components, can also be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to be PI3Kγinhibitors according to at least one assay described herein.

EXAMPLES

Preparatory LC-MS purifications of some of the compounds prepared wereperformed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature (see e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004)). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity analysis under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm, 2.1×50 mm, Buffers: mobile phase A: 0.025% TFA in water and mobilephase B: acetonitrile; gradient 2% to 80% of B in 3 minutes with flowrate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature (see e.g.“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J Comb. Chem., 6,874-883 (2004)). Typically, the flow rate used with the 30×100 mm columnwas 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.15% NH₄OH in water and mobile phase B:acetonitrile; the flow rate was 30 mL/minute, the separating gradientwas optimized for each compound using the Compound Specific MethodOptimization protocol as described in the literature (see e.g.“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)). Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results.

Example 1.3-(8-Aminoimidazo[1,2-a]pyridin-3-yl)-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamidetrifluoroacetate

Step 1. 3-Bromo-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

To a mixture of trans-4-aminocyclohexanol (0.47 g, 4.1 mmol),4-dimethylaminopyridine (9 mg, 0.07 mmol), and triethylamine (1.0 mL,7.4 mmol) in DCM (20 mL) at 0° C. was added3-bromo-4-methylbenzenesulfonyl chloride (1.0 g, 3.7 mmol)(Combi-Blocks, WZ-9240) in a single portion. The reaction mixture wasstirred overnight while coming to room temperature. The reaction wasthen quenched with sat. NaHCO₃. The organic layer was removed, and theaqueous layer was extracted with DCM (2×). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated. Purification viasilica gel chromatography (20-75% EtOAc in DCM (1% MeOH)) afforded thetitle compound as a white solid (0.94 g, 73%). LCMS for C₁₃H₁₈BrNO₃SNa(M+Na)⁺: calculated m/z=370.0, 372.0; found 370.0, 372.0.

Step 2.N-(trans-4-Hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

Two microwave vials were each charged with a mixture of3-bromo-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide (0.47g, 1.4 mmol), bis(pinacolato)diboron (0.43 g, 1.7 mmol), KOAc (0.43 g,4.4 mmol), and dichloro[bis(triphenylphosphoranyl)]palladium (38 mg,0.055 mmol). THF (25 mL) was added to each vial, and the reactionmixtures were degassed with N₂ for 5 min. The reaction mixtures werethen heated at 140° C. in a microwave for 20 min. The reaction mixtureswere diluted with EtOAc, combined, and filtered through Celite. TheCelite was then rinsed with EtOAc. The filtrate was washed with waterand then brine, dried over Na₂SO₄, filtered, and concentrated.Purification via silica gel chromatography (1-7% MeOH in DCM) affordedthe title compound a white solid (1.3 g, >99%). LCMS for C₁₉H₃₁BNO₅S(M+H)⁺: calculated m/z=396.2; found 396.2.

Step 3.3-(8-Aminoimidazo[1,2-a]pyridin-3-yl)-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamidetrifluoroacetate

A 1-dram vial was charged with 3-bromoimidazo[1,2-a]pyridin-8-amine (2mg, 0.009 mmol) (Synthonix, B0590),N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide(3.5 mg, 0.0088 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1 mg, 0.002 mmol). THF (0.12 mL) and then 1.0 MK₂CO₃ in water (22 μL, 0.022 mmol) were added. The reaction mixture wasdegassed with N₂ briefly and subsequently heated at 80° C. overnight.The reaction mixture was diluted with MeOH and filtered through Celite.Purification via preparative HPLC on a C-18 column (pH 2, 12-32%MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded the title compound asan off-white solid (1.8 mg, 40%). LCMS for C₂₀H₂₅N₄O₃S (M+H)⁺:calculated m/z=401.2; found 401.1.

Example 2.A-[5-(8-Aminoimidazo[1,2-a]pyridin-3-yl)-2-fluoropyridin-3-yl]ethanesulfonamidebis(trifluoroacetate)

Step 1. N-(5-bromo-2-fluoropyridin-3-yl)ethanesulfonamide

To a solution of 5-bromo-2-fluoropyridin-3-amine (3 g, 20 mmol) inpyridine (10 mL) and DCM (20 mL) at room temperature was addedethanesulfonyl chloride (2.2 mL, 24 mmol). After stirring for 30 min,the solvent was evaporated. The resulting residue was diluted with MeOH(4 mL) and partitioned between EtOAc and brine. The organic layer wasseparated, and the aq. layer was extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated.Purification via silica gel chromatography afforded the title compound(2 g, 40%). LCMS for C₇H₉BrFN₂O₂S (M+H)⁺: calculated m/z=283.0, 285.0;found 283.0, 284.9.

Step 2.N—[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]ethane sulfonamide

A mixture of bis(pinacolato)diboron (0.77 g, 3.0 mmol),N-(5-bromo-2-fluoropyridin-3-yl)ethanesulfonamide (1.0 g, 0.32 mmol),and KOAc (1.3 g, 13 mmol) in 1,4-dioxane (50 mL,) was degassed by N₂ for5 min. Then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (260 mg, 0.32 mmol) was added, and theresultant mixture was heated for 1 h at 120° C. The crude mixture wasfiltered through Celite to afford the title compound as a solution in1,4-dioxane. LCMS for C₁₃H₂₁BFN₂O₄S (M+H)⁺: calculated m/z=331.1; found331.0.

Step 3.N—[5-(8-Aminoimidazo[1,2-a]pyridin-3-yl)-2-fluoropyridin-3-yl]ethanesulfonamidebis(trifluoroacetate)

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 1, Step 3 substituting asolution ofN-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]ethanesulfonamidein 1,4-dioxane forN-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide.LCMS for C₁₄H₁₅FN₅O₂S (M+H)⁺: calculated m/z=336.1; found 336.1.

Example 3.3-(8-Aminoimidazo[1,2-a]pyridin-3-yl)-4-methyl-/V-[(3-methyloxetan-3-yl)methyl]benzenesulfonamidetrifluoroacetate

Step 1.3-Bromo-4-methyl-N-[(3-methyloxetan-3-yl)methyl]benzenesulfonamide

To a solution of 3-bromo-4-methylbenzenesulfonyl chloride (500.0 mg,1.855 mmol) (Combi-Blocks, WZ-9240) in THE (10.0 mL) and pyridine (0.300mL, 3.71 mmol) was added 1-(3-methyloxetan-3-yl)methanamine (225 mg,2.22 mmol) (Combi-Blocks, SS-0093). The resulting mixture was stirred atroom temperature overnight. The reaction mixture was then concentratedin vacuo. The resulting residue was added to 1.0 N HCl (100 mL) andextracted with EtOAc (2×100 mL). The combined organic layers were washedwith sat. Na₂CO₃ solution (100 mL) and brine, dried over MgSO₄,filtered, and concentrated. Purification via on silica gelchromatography (10-80% EtOAc/hexanes) afforded the title compound (296.0mg, 48%). LCMS for C₁₂H₁₇BrNO₃S (M+H)⁺: calculated m/z=334.0, 336.0;found 333.9, 335.9.

Step 2.4-Methyl-N-[(3-methyloxetan-3-yl)methyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

To a vial was added3-bromo-4-methyl-N-[(3-methyloxetan-3-yl)methyl]benzenesulfonamide (296mg, 0.886 mmol), KOAc (156 mg, 1.59 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (36.2 mg, 0.0443 mmol), bis(pinicolato)diboron (337mg, 1.33 mmol), and 1,2-dimethoxyethane (4.43 mL, 42.6 mmol). Themixture was degassed by bubbling N₂ for 10 minutes. The vial was thensealed, and the reaction mixture was heated at 90° C. for 2 h. Thereaction mixture was then poured into water and extracted with EtOAc.The organic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated. Purification via silica gel chromatography (10-40% EtOAc[5% MeOH]/hexanes) afforded the title compound (96.0 mg, 31%). LCMS forC₁₈H₂₉BNO₅S (M+H)⁺: calculated m/z=382.2; found 382.2.

Step 3.3-(8-Aminoimidazo[1,2-a]pyridin-3-yl)-4-methyl-N-[(3-methyloxetan-3-yl)methyl]benzenesulfonamidetrifluoroacetate

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 1, Step 3 substituting4-methyl-N-[(3-methyloxetan-3-yl)methyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamideforN-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide.¹H NMR (400 MHz, d₆-DMSO) δ 8.22 (s, 1H), 8.06-7.80 (m, 3H), 7.73 (dd,J=8.3, 4.7 Hz, 1H), 7.47 (d, J=6.7 Hz, 1H), 7.12 (t, j=7.0 Hz, 1H), 6.89(d, J=7.4 Hz, 1H), 6.26 (s, 2H), 4.30 (d, J=5.9 Hz, 2H), 4.17 (d, J=5.9Hz, 2H), 2.97 (d, J=6.5 Hz, 2H), 2.25 (s, 3H), 1.19 (s, 3H). LCMS forC₁₉H₂₃N₄O₃S (M+H)⁺: calculated m/z=387.1; found 387.1.

Example 4.3-(8-Amino-6-chloroimidazo[1,2-a]pyridin-3-yl)-N′-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamidetrifluoroacetate

Step 1. 6-Chloroimidazo[1,2-a]pyridin-8-amine

To a solution of 5-chloro-2,3-diaminopyridine (1 g, 7 mmol) in ethanol(50 mL) was slowly added chloroacetaldehyde (3.5 mL, 27 mmol, 50% inH₂O). The reaction mixture was refluxed for 6 h. Heating wasdiscontinued, and the reaction mixture was stirred overnight. Thereaction mixture was concentrated. Et₂O was added to the resultingresidue, and the solvent was removed in vacuo. The resulting oil wasdissolved in water, and the aqueous layer was basified by addition of 1M NaOH (aq). The aqueous layer was then extracted with DCM (3 x). Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated. Purification via silica gel chromatography (1-10% MeOH inDCM) afforded the title compound as a light brown solid (0.9 g, 80%). ¹HNMR (600 MHz, d₆-DMSO) δ 7.99 (d, J=1.9 Hz, 1H), 7.79 (d, J=1.1 Hz, 1H),7.45 (d, J=1.1 Hz, 1H), 6.21 (d, J=1.9 Hz, 1H), 6.01 (s, 2H). LCMS forC₇H₇ClN₃ (M+H)⁺: calculated m/z=168.0; found 168.1.

Step 2. N-(6-Chloroimidazo[1,2-a]pyridin-8-yl)acetamide

To a solution of 6-chloroimidazo[1,2-a]pyridin-8-amine (0.25 g, 1.5mmol) and 4-dimethylaminopyridine (5 mg, 0.04 mmol) in DCM (10 mL) at 0°C. was added triethylamine (0.63 mL, 4.5 mmol) and then acetic anhydride(0.21 mL, 2.2 mmol). After coming to room temperature, the reactionmixture was stirred overnight. The reaction mixture was again cooled to0° C. Additional portions of 4-dimethylaminopyridine (7 mg, 0.06 mmol),triethylamine (0.63 mL, 4.5 mmol), and acetic anhydride (0.21 mL, 2.2mmol) were added. After coming to room temperature, the reaction mixturewas stirred overnight. The reaction mixture was diluted with DCM andwashed with sat. NaHCO₃ (aq), water, and then brine. The organic layerwas dried over Na₂SO₄, filtered, and concentrated. Purification viasilica gel chromatography (17-100% EtOAc in hexanes, then 1-10% MeOH inEtOAc) afforded the title compound as a brown solid (0.12 g, 38%). LCMSfor C₉H₉ClN₃O (M+H)⁺: calculated m/z=210.0; found 210.0.

Step 3. N-(3-Bromo-6-chloroimidazo[1,2-a]pyridin-8-yl)acetamide

To a solution of N-(6-chloroimidazo[1,2-a]pyridin-8-yl)acetamide (50.mg, 0.24 mmol) in DCM (6 mL) was added N-bromosuccinimide (43 mg, 0.24mmol). The reaction mixture was stirred at room temperature for 30 min.The mixture was then washed with Na₂CO₃ (10% aq), dried over Na₂SO₄,filtered, and concentrated. Purification via silica gel chromatography(1-10% MeOH in DCM) afforded the title compound as a tan solid (56 mg,81%). ¹H NMR (600 MHz, CDCl₃) δ 8.49 (s, 1H), 8.27 (d, J=1.6 Hz, 1H),7.89 (d, J=1.7 Hz, 1H), 7.51 (s, 1H), 2.30 (s, 3H). LCMS for C₉H₈BrClN₃O(M+H)⁺: calculated m/z=288.0, 289.9; found 288.0, 290.0.

Step 4.3-(8-Amino-6-chloroimidazo[1,2-a]pyridin-3-yl)-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamidetrifluoroacetate

A 1-dram vial was charged withN-(3-bromo-6-chloroimidazo[1,2-a]pyridin-8-yl)acetamide (10. mg, 0.035mmol),N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide(Example 1, Step 2, 17 mg, 0.043 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (6 mg, 0.007 mmol). THE (0.50 mL) and then 1.0 MK₂CO₃ in water (87 μL, 0.087 mmol) were added. The reaction mixture wasdegassed with N₂ for 5 min and subsequently heated at 80° C. overnight.The reaction mixture was then diluted with MeOH and filtered through aplug of Na₂SO₄ and Celite, rinsing with MeOH. The filtrate wasconcentrated.

The resulting residue was dissolved in 10:1 EtOH/conc. HCl (1.0 mL), andthe reaction mixture was heated at 80° C. for 2 h. The reaction mixturewas diluted with MeOH and filtered via syringe filter. Purification viapreparative HPLC on a C-18 column (pH 2, 15-35% MeCN/0.1% TFA (aq) over5 min, 60 mL/min) afforded the title compound as a white solid (9.5 mg,50%). LCMS for C₂₀H₂₄ClN₄O₃S (M+H)⁺: calculated m/z=435.1; found 435.2.

Example 5.N—[6-chloro-3-(5-{[(trans-4-hydroxycyclohexyl)amino]sulfonyl}-2-methylphenyl)imidazo[1,2-a]pyridin-8-yl]acetamide

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 1, Step 3 substitutingN-(3-bromo-6-chloroimidazo[1,2-a]pyridin-8-yl)acetamide for3-bromoimidazo[1,2-a]pyridin-8-amine. Purification via preparative HPLCon a C-18 column (pH 10, 26-46% MeCN/0.1% NH₄OH (aq) over 5 min, 60mL/min) afforded the title compound as a white residue (3.4 mg). LCMSfor C₂₂H₂₆ClN₄O₄S (M+H)⁺: calculated m/z=477.1; found 477.1.

Example 6.7V-[5-(8-Amino-6-chloroimidazo[1,2-a]pyridin-3-yl)-2-oxo-1,2-dihydropyridin-3-yl]ethanesulfonamidetrifluoroacetate; and Example 7.N—[5-(8-Amino-6-chloroimidazo[1,2-a]pyridin-3-yl)-2-ethoxypyridin-3-yl]ethanesulfonamidebis(trifluoroacetate)

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 4, Step 4 substituting a solutionofN—[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]ethanesulfonamidein 1,4-dioxane (Example 2, Step 2) forN-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide.Purification via preparative HPLC on a C-18 column (pH 2, 15-41%MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded Example 6 as a whitesolid (4.7 mg, first to elute, t_(R)=3.2 min) and Example 7 as anoff-white solid (2.8 mg, second to elute, t_(R)=5.1 min). Example 6:LCMS for C₁₄H₁₅ClN₅O₃S (M+H)⁺: calculated m/z=368.1; found 368.1.Example 7: LCMS for C₁₈H₁₉ClN₅C₃S (M+H)⁺: calculated m/z=396.1; found396.1.

Example 8.3-[8-Amino-6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamidebis(trifluoroacetate)

A 1-dram vial was charged withN-(3-bromo-6-chloroimidazo[1,2-a]pyridin-8-yl)acetamide (Example 4, Step3, 30.7 mg, 0.106 mmol),N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide(Example 1, Step 2, 52 mg, 0.13 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (18 mg, 0.022 mmol). THE (1.6 mL) and then 1.0 MK₂CO₃ in water (0.27 mL, 0.27 mmol) were added. The reaction mixture wasdegassed with N₂ for 5 min and subsequently heated at 80° C. for 4 h. Anadditional portion ofN-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide(15 mg, 0.038 mmol) was added, and the reaction mixture was subsequentlyheated at 80° C. for 3 h. The reaction mixture was diluted with MeOH andfiltered through a plug of Na₂SO₄ and Celite, rinsing with MeOH. Thefiltrate was concentrated to afford the crude intermediate.

To 1-dram vial was added a portion of the crude intermediate (10 mg),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(9.3 mg, 0.045 mmol),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(1 mg, 0.001 mmol), 1-butanol (0.2 mL), CsF (11 mg, 0.072 mmol), andwater (42 μL). The mixture degassed with N₂ for 5 min. The vial wascapped, and the reaction mixture was heated at 100° C. for 1.5 h.Heating was discontinued, and the reaction mixture was stirredovernight. The reaction mixture was diluted with MeOH and filteredthrough a plug of Na₂SO₄ and Celite, rinsing with MeOH.

The resulting residue was dissolved in 10:1 EtOH/conc. HCl (0.61 mL),and the reaction mixture was heated at 80° C. for 1 h. The reactionmixture was diluted with MeOH and filtered via syringe filter.Purification via preparative HPLC on a C-18 column (pH 2, 14-34%MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded the title compound asa white solid (3.6 mg). LCMS for C₂₄H₂₉N₆O₃S (M+H)⁺: calculatedm/z=481.2; found 481.2.

Example 9 and Example 10

Examples 9 and 10 were synthesized according to procedures analogous tothe synthesis of Example 8, and the data are listed in Table 1.

TABLE 1

Ex. LCMS No. Name R⁸ [M + H]⁺  9 3-(8-Amino-6-pyrimidin-5-ylimidazo[1,2-a]pyridin-3- yl)-N-(trans-4- hydroxycyclohexyl)-4-methylbenzenesulfonamide

479.1 10 3-[8-Amino-6-(1-methyl- 1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-3- yl]-N-(trans-4- hydroxycyclohexyl)-4-methylbenzenesulfonamide bis(trifluoroacetate)

481.2

Example 11.3-(8-Amino-7-chloroimidazo[1,2-a]pyridin-3-yl)-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamidetrifluoroacetate

Step 1. 7-Chloroimidazo[1,2-a]pyridin-8-amine

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 4, Step 1, substituting4-chloro-2,3-diaminopyridine (Synthonix, D0349) for5-chloro-2,3-diaminopyridine. LCMS for C₇H₇ClN₃ (M+H)⁺: calculatedm/z=168.0; found 168.0.

Step 2. N-Acetyl-N-(7-chloroimidazo[1,2-a]pyridin-8-yl)acetamide

To a solution of 7-chloroimidazo[1,2-a]pyridin-8-amine (0.50 g, 3.0mmol) and 4-dimethylaminopyridine (37 mg, 0.30 mmol) in DCM (20 mL) at0° C. was added triethylamine (2.5 mL, 18 mmol) and then aceticanhydride (0.84 mL, 9.0 mmol). After coming to room temperature, thereaction mixture was stirred overnight at room temperature. The reactionmixture was then cooled to 0° C., and acetyl chloride (0.42 mL, 6.0mmol) was added dropwise. The reaction mixture was warmed to roomtemperature, stirred for 3 h, and then heated at reflux for 4 h. Thereaction mixture was diluted with DCM and washed successively with sat.NaHCO₃, water, and brine. The organic layer was dried over Na₂SO₄,filtered, and concentrated. Purification via silica gel chromatography(1-10% MeOH in DCM) afforded the title compound as a brown solid (0.68g, 90%). LCMS for C₁₁H₁₁ClN₃O₂(M+H)⁺: calculated m/z=252.1; found 252.0.

Step 3. N-Acetyl-N-(3-bromo-7-chloroimidazo[1,2-a]pyridin-8-yl)acetamide

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 4, Step 3, substitutingN-acetyl-N-(7-chloroimidazo[1,2-a]pyridin-8-yl)acetamide forN-(6-chloroimidazo[1,2-a]pyridin-8-yl)acetamide. LCMS forC₁₁H₉BrClN₃NaO₂ (M+Na)⁺: calculated m/z=352.0, 353.9; found 351.8,353.8.

Step 4.3-(8-Amino-7-chloroimidazo[1,2-a]pyridin-3-yl)-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamidetrifluoroacetate

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 4, Step 4, substitutingN-acetyl-N-(3-bromo-7-chloroimidazo[1,2-a]pyridin-8-yl)acetamide forN-(3-bromo-6-chloroimidazo[1,2-a]pyridin-8-yl)acetamide. ¹H NMR (600MHz, CD₃OD) δ 8.13 (s, 1H), 8.01 (dd, J=8.2, 2.0 Hz, 1H), 7.96 (d, J=2.0Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.49 (d, J=7.1 Hz, 1H), 7.35 (d, J=7.1Hz, 1H), 3.52-3.39 (m, 1H), 3.10-3.01 (m, 1H), 2.29 (s, 3H), 1.86(apparent d, J=12.0 Hz 2H), 1.77 (apparent d, J=11.9 Hz, 2H), 1.33-1.17(m, 4H). LCMS for C₂₀H₂₄ClN₄O₃S (M+H)⁺: calculated m/z=435.1; found435.1.

Example 12.3-[8-Amino-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

Step 1.N—[7-Chloro-3-(5-{[(trans-4-hydroxycyclohexyl)amino]sulfonyl}-2-methylphenyl)imidazo[1,2-a]pyridin-8-yl]acetamide

A 1-dram vial was charged withN-acetyl-N-(3-bromo-7-chloroimidazo[1,2-a]pyridin-8-yl)acetamide(Example 11, Step 3, 18 mg, 0.054 mmol),N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide(Example 1, Step 2, 27 mg, 0.068 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (9 mg, 0.01 mmol). THF (0.81 mL) and then 1.0 MK₂CO₃ in water (0.14 mL, 0.14 mmol) were added. The reaction mixture wasdegassed with N₂ for 5 min and subsequently heated at 80° C. overnight.Additional portions ofN-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide(28 mg, 0.071 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (9 mg, 0.01 mmol) were added. The reaction mixturewas degassed briefly and subsequently heated at 80° C. for 5 h. Thereaction mixture was diluted with DCM and washed successively with waterand brine. The organic layer was filtered through a plug of Na₂SO₄ andconcentrated. Purification via silica gel chromatography (5-20% MeOH inDCM) afforded the title compound as a brown solid (27 mg). LCMS forC₂₂H₂₆ClN₄O₄S (M+H)+: calculated m/z=477.1; found 477.1.

Step 2. 3-[8-Amino-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

To 1-dram vial was addedN—[7-chloro-3-(5-{[(trans-4-hydroxycyclohexyl)amino]sulfonyl}-2-methylphenyl)imidazo[1,2-a]pyridin-8-yl]acetamide(8.7 mg, 0.018 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9mg, 0.04 mmol),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(1 mg, 0.001 mmol), 1-butanol (0.2 mL), CsF (11 mg, 0.072 mmol), andwater (36 μL, 2.0 mmol). The solvent degassed with N₂ for 5 min. Thevial was capped, and the mixture was heated at 100° C. for 1.5 h. Thereaction mixture was diluted with MeOH and filtered through a plug ofNa₂SO₄ and Celite. The filtrate was concentrated.

The resulting residue was dissolved in 10:1 EtOH/conc. HCl (0.53 mL),and the reaction mixture was heated at 80° C. for 8 h. The reactionmixture was diluted with MeCN and filtered via syringe filter.Purification via preparative HPLC on a C-18 column (pH 2, 15-35%MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded a yellow residue (3.3mg). This residue was partitioned between DCM and 1 M NaOH (aq). Theorganic layer was removed, and the aqueous layer extracted with DCM (2x). The organic layers were filtered through a plug of Na₂SO₄ andconcentrated to afford the title compound as a white residue (0.9 mg).LCMS for C₂₄H₂₉N₆O₃S (M+H)⁺: calculated m/z=481.2; found 481.1.

Example 13.3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

A microwave vial was charged with 3-bromoimidazo[1,2-a]pyrazin-8-amine(50. mg, 0.23 mmol),N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide(Example 1, Step 2, 110 mg, 0.28 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (38 mg, 0.047 mmol). THF (3.5 mL) and then 1.0 MK₂CO₃ in water (0.58 mL, 0.58 mmol) were added. The reaction mixture wasdegassed with N₂ for 5 min and subsequently heated at 80° C. overnight.The reaction mixture was poured into 50% sat. NaCl (10 mL) and extractedwith DCM (3×10 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated. Purification via preparative HPLC on a C-18column (pH 10, 20-33% MeCN/0.1% NH₄OH (aq) over 5 min, 60 mL/min)afforded a white solid (41 mg, 44%). ¹H NMR (600 MHz, d₆-DMSO) δ 7.83(dd, J=8.1, 2.0 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.68 (s, 1H), 7.65 (d,J=8.2 Hz, 1H), 7.63 (br s, 1H), 7.25 (d, J=4.7 Hz, 1H), 7.18 (d, J=4.7Hz, 1H), 7.03 (s, 2H), 4.47 (d, J=4.2 Hz, 1H), 3.34-3.24 (m, 1H),2.98-2.89 (m, 1H), 2.25 (s, 3H), 1.74-1.68 (m, 2H), 1.64-1.57 (m, 2H),1.22-1.12 (m, 2H), 1.12-1.02 (m, 2H), LCMS for C₁₉H₂₄N₅O₃S (M+H)⁺:calculated m/z=402.2; found 402.2.

Example 14.N—[5-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-2-fluoropyridin-3-yl]ethanesulfonamidebis(trifluoroacetate)

To a 1-dram vial was added 3-bromoimidazo[1,2-a]pyrazin-8-amine (10. mg,0.047 mmol) (Synthonix, A11597), a solution ofN—[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]ethanesulfonamide(Example 2, Step 2, 31 mg, 0.094 mmol) in 1,4-dioxane (1.2 mL, 15 mmol),and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (8 mg, 0.009 mmol). THF (0.70 mL, 8.6 mmol) andthen 1.0 M K₂CO₃ in water (0.12 mL, 0.12 mmol) were added. The reactionmixture was degassed with N₂ for 5 min and subsequently heated at 80° C.overnight. The reaction mixture was diluted with MeOH and filteredthrough Celite. Purification via preparative HPLC on a C-18 column (pH2, 15-35% MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded the titlecompound as a white solid (9.5 mg, 36%). ¹H NMR (600 MHz, d₆-DMSO) δ10.24 (br s, 1H), 8.86 (br s, 2H), 8.31 (dd, J=2.0, 1.1 Hz, 1H), 8.14(dd, J=9.3, 2.2 Hz, 1H), 8.04 (s, 1H), 7.81 (d, J=5.5 Hz, 1H), 7.35 (d,J=5.5 Hz, 1H), 3.28 (q, J=7.3 Hz, 2H), 1.28 (t, J=7.3 Hz, 3H). LCMS forC₁₃H₁₄FN₆O₂S (M+H)⁺: calculated m/z=337.1; found 337.1.

Example 15.3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-4-methyl-N-[(3-methyloxetan-3-yl)methyl]benzenesulfonamidetrifluoroacetate

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 14, substituting4-methyl-N-[(3-methyloxetan-3-yl)methyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamidefor a solution ofN—[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]ethanesulfonamidein 1,4-dioxane. LCMS for C₁₈H₂₂N₅O₃S (M+H)⁺: calculated m/z=388.1; found388.1.

Example 16.3-(8-Amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

Step 1. 6,8-Dibromo-3-iodoimidazo[1,2-a]pyrazine

To a solution of 6,8-dibromoimidazo[1,2-a]pyrazine (0.50 g, 1.8 mmol)(Combi-Blocks, OR-7964) in DMF (12 mL) was added N-iodosuccinimide (0.45g, 2.0 mmol). The reaction mixture was then heated at 60° C. for 15.5 h.The reaction mixture was concentrated in vacuo. The resulting solid wastaken up into DCM. The organic layer was washed sequentially with waterand sat. Na₂S₂O₃ (aq). The organic layer was then dried over Na₂SO₄,filtered, and concentrated to afford the title compound as a lightyellow solid (0.64 g, 88%). LCMS for C₆H₃Br₂IN₃ (M+H)⁺: calculatedm/z=401.8, 403.8, 405.8; found 401.8, 403.7, 405.6.

Step 2. 6-Bromo-3-iodoimidazo[1,2-a]pyrazin-8-amine

A suspension of 6,8-dibromo-3-iodoimidazo[1,2-a]pyrazine (539 mg, 1.34mmol) in conc. NH₄OH (aq) (10 mL) was heated at 150° C. for 15 min in amicrowave. After cooling to 0° C., the reaction mixture was diluted withcold water and filtered. The collected solid was then washed with coldwater to afford the title compound as an off-white solid (356 mg, 79%).LCMS for C₆H₅BrIN₄ (M+H)⁺: calculated m/z=338.9, 340.9; found 338.8,340.9.

Step 3.3-(8-Amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

A mixture of 6-bromo-3-iodoimidazo[1,2-a]pyrazin-8-amine (Example 16,Step 2, 0.20 g, 0.59 mmol),N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide(Example 1, Step 2, 0.26 g, 0.65 mmol),tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.039 mmol), ethanol (8mL, 100 mmol), and 2.0 M Na₂CO₃ in water (0.59 mL, 1.2 mmol) wasdegassed for 5 min with N₂. The reaction mixture was then heated at 130°C. for 20 min in a microwave. The reaction mixture was diluted with DCMand water. The biphasic mixture was filtered through a plug of Celite.The organic layer was removed from the filtrate, and the aqueous layerwas extracted with DCM (2 x). The combined organic layers were washedwith brine, dried over MgSO₄, filtered, and concentrated. Purificationvia silica gel chromatography (1-20% MeOH in DCM) afforded a white solid(0.12 g, 42%). LCMS for C₁₉H₂₂BrN₅O₃S (M+H)⁺: calculated m/z=480.1,482.1; found 480.0, 482.0.

Example 17.3-[8-Amino-6-(2-methylphenyl)imidazo[1,2-a]pyrazin-3-yl]-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

A 1-dram vial was charged with3-(8-amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide(Example 16, 6 mg, 0.01 mmol), (2-methylphenyl)boronic acid (3 mg, 0.02mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (2 mg, 0.002 mmol). THF (0.2 mL) and then1.0 M K₂CO₃ in water (31 μL, 0.031 mmol) were added. The reactionmixture was degassed with N₂ briefly and then heated at 80° C. for 16 h.Heating was discontinued, and the reaction mixture was stirred for 2days. The reaction mixture was diluted with MeOH and filtered throughCelite. The filtrate was concentrated. Purification via preparative HPLCon a C-18 column (pH 10, 28-48% MeCN/0.1% NH₄OH (aq) over 5 min, 60mL/min) afforded the title compound as a white solid (3 mg, 50%).

¹H NMR (600 MHz, d₆-DMSO) δ 7.84-7.79 (m, 2H), 7.73 (s, 1H), 7.63 (d,J=8.7 Hz, 1H), 7.34 (d, J=7.2 Hz, 1H), 7.28-7.22 (m, 2H), 7.19 (td,J=7.1, 1.9 Hz, 1H), 7.15 (s, 1H), 7.14 (br s, 2H), 4.43 (d, J=4.2 Hz,1H), 3.28-3.16 (m, 1H), 2.98-2.85 (m, 1H), 2.34 (s, 3H), 2.29 (s, 3H),1.70-1.61 (m, 2H), 1.61-1.51 (m, 2H), 1.22-1.07 (m, 2H), 1.07-0.93 (m,2H). LCMS for C₂₆H₃₀N₅O₃S (M+H)⁺: calculated m/z=492.2; found 492.2.

Examples listed in Table 2 were synthesized according to proceduresanalogous to the synthesis of Example 17.

TABLE 2

LCMS Ex. Name R⁸ [M + H]⁺ No. ¹H NMR Spectrum 18 3-[8-Amino-6-(4-methylphenyl)imidazo[1,2- a]pyrazin-3-yl]-N-(trans-4-hydroxycyclohexyl)-4- methylbenzenesulfonamide

492.2 19 3-[8-Amino-6-(3- methylphenyl)imidazo[1,2-a]pyrazin-3-yl]-N-(trans-4- hydroxycyclohexyl)-4-methylbenzenesulfonamide

492.2 20 3-[8-Amino-6-(4- fluorophenyl)imidazo[1,2-a]pyrazin-3-yl]-N-(trans-4- hydroxycyclohexyl)-4-methylbenzenesulfonamide

496.1 ¹H NMR (400 MHz, d₆-DMSO) δ 7.96-7.89 (m, 2H), 7.88-7.80 (m, 2H),7.70-7.61 (m, 3H), 7.26-7.15 (m, 3H), 4.48 (d, J = 4.1 Hz, 1H),3.39-3.20 (m, 1H), 2.94 (br s, 1H), 2.28 (s, 3H), 1.81-1.54 (m, 4H),1.28-0.91 (m, 4H). 21 3-[8-Amino-6-(3- fluorophenyl)imidazo[1,2-a]pyrazin-3-yl]-N-(trans-4- hydroxycyclohexyl)-4-methylbenzenesulfonamide

496.1 ¹H NMR (400 MHz, d₆-DMSO) δ 7.89-7.80 (m, 2H), 7.78-7.63 (m, 6H),7.47-7.38 (m, 1H), 7.25 (s, 2H), 7.16 (t, J = 8.3 Hz, 1H), 4.46 (d, J =3.6 Hz, 1H), 3.40-3.20 (m, 1H), 2.95 (br s, 1H), 2.28 (s, 3H), 1.65 (m,4H), 1.27-0.97 (m, 4H). 22 3-[8-Amino-6-(2- fluorophenyl)imidazo[1,2-a]pyrazin-2-yl]-N-(trans-4- hydroxycyclohexyl)-4-methylbenzenesulfonamide

496.1 ¹H NMR (400 MHz, d₆-DMSO) δ 8.07 (td, J = 8.0, 1.7 Hz, 1H),7.87-7.79 (m, 2H), 7.74 (s, 1H), 7.71-7.60 (m, 3H), 7.38 (s, 1H),7.33-7.17 (m, 4H), 4.46 (d, J = 4.1 Hz, 1H), 3.39-3.19 (m, 1H), 2.92 (brs, 1H), 2.29 (s, 3H), 1.75-1.63 (m, 2H), 1.63-1.51 (m, 2H), 1.25-0.97(m, 4H). 23 3-[8-Amino-6- phenylimidazo[1,2-a]pyrazin-3- yl]-N-(trans-4-hydroxycyclohexyl)-4- methylbenzenesulfonamide

478.2 ¹H NMR (400 MHz, d₆-DMSO) δ 7.90-7.82 (m, 4H), 7.72-7.58 (m, 4H),7.40 (t, J = 7.3 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.20 (s, 2H), 4.47(d, J = 4.4 Hz, 1H), 3.37-3.21 (m, 1H) 2.95 (s, 1H), 2.29 (s, 3H) 1.65(m, 4H), 1.26-0.96 (m, 4H). 24 3-[8-Amino-6-(4- cyanophenyl)imidazo[1,2-a]pyrazin-2-yl]-N-(trans-4- hydroxycyclohexyl)-4-methylbenzenesulfonamide

503.2 25 3-(8-Amino-6-pyridin-4- ylimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexyl)- 4-methylbenzenesulfonamide

479.2 26 3-(8-Amino-6-pyridin-3- ylimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexyl)- 4-methylbenzenesulfonamide

479.1 ¹H NMR (400 MHz, d₆-DMSO) δ 9.08 (d, J = 2.3 Hz, 1H), 8.52 (dd, J= 4.7, 1.6 Hz, 1H), 8.23 (dt, J = 8.0, 1.9 Hz, 1H), 7.88-7.81 (m, 2H),7.78 (s, 1H), 7.70 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.42 (dd, J = 8.0,4.8 Hz, 1H), 7.29 (s, 2H), 4.46 (d, J = 3.1 Hz, 1H), 3.43-3.19 (m, 1H),2.95 (s, 1H), 2.28 (s, 3H), 1.62 (s, 4H), 1.24-0.95 (m, 4H). 273-[8-Amino-6-(2- thienyl)imidazo[1,2-a]pyrazin- 3-yl]-N-(trans-4-hydroxycyclohexyl)-4- methylbenzenesulfonamide

484.1 28 3-[8-Amino-6-(1-methyl-1H- pyrazol-5-yl)imidazo[1,2-a]pyrazin-3-yl]-N-(trans-4- hydroxycyclohexyl)-4-methylbenzenesulfonamide

482.2 29 3-[8-Amino-6-(1-methyl-1H- pyrazol-4-yl)imidazo[1,2-a]pyrazin-3-yl]-N-(trans-4- hydroxycyclohexyl)-4-methylbenzenesulfonamide

482.2 30 3-[8-Amino-6-(2-fluoro-3- methoxyphenyl)imidazo[1,2-a]pyrazin-3-yl]-N-(trans-4- hydroxycyclohexyl)-4-methylbenzenesulfonamide

526.2 31 3-[8-Amino-3-(5-{[(trans-4- hydroxycyclohexyl)amino]sulfonyl}-2- methylphenyl)imidazo[1,2- a]pyrazin-6-yl]-4-fluoro-N-methylbenzamide

553.2 32 3-{8-Amino-6-[2-fluoro-4- (hydroxymethyl)phenyl]imidazo[1,2-a]pyrazin-3-yl}-N- (trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

526.2 33 3-{8-Amino-6-[3- (methylsulfonyl)phenyl]imidazo[1,2-a]pyrazin-3-yl}-N- (trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

526.2 34 3-[8-Amino-6-(2-fluoro-6- methoxyphenyl)imidazo[1,2-a]pyrazin-3-yl]-N-(trans-4- hydroxycyclohexyl)-4-methylbenzenesulfonamide

556.2 35 3-[8-Amino-6-(2-methylthiazol- 5-yl)imidazo[1,2-a]pyrazin-3-yl]-N-(trans-4- hydroxycyclohexyl)-4- methylbenzenesulfonamide

499.2 ¹H NMR (400 MHz, d₆-DMSO) δ 7.99 (s, 1H), 7.84 (d, J = 8.0 Hz,1H), 7.79 (s, 1H) 7.70-7.59 (m, 3H), 7.29 (s, 2H), 4.68-4.21 (m, 1H),3.05-2.83 (m, 1H), 2.62 (s, 3H), 2.25 (s, 3H), 1.85-1.53 (m, 4H),1.33-0.93 (m, 4H). 75 3-[8-amino-6-(3- methylisoxazol-5-yl)imidazo[1,2-a]pyrazin-3-yl]- N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

483.2 ¹H NMR (600 MHz, DMSO-d₆) δ 7.86 (dd, J = 8.1, 1.9 Hz, 1H), 7.81(d, J = 1.7 Hz, 1H), 7.75 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.63 (s,1H), 7.40 (s, 2H), 6.65 (s, 1H), 4.50-4.36 (m, 1H), 3.40-3.32 (m, 1H),3.02-2.89 (m, 1H), 2.26 (s, 3H), 2.25 (s, 3H), 1.75-1.66 (m, 2H),1.66-1.57 (m, 2H), 1.28-1.12 (m, 2H), 1.12-1.00 (m, 2H). 763-{8-amino-6-[1-(2,2,2- trifluoroethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-3-yl}- N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

550.4 ¹H NMR (400 MHz, DMSO-d₆) δ 8.16 (s, 1H), 7.93 (s, 1H), 7.84 (d, J= 8.1 Hz, 1H), 7.77 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.61 (s, 1H),7.52 (s, 1H), 7.11 (s, 2H), 5.13 (q, J = 9.0 Hz, 2H), 4.55-4.35 (m, 1H),3.03-2.83 (m, 1H), 2.24 (s, 3H), 1.80-1.53 (m, 4H), 1.28-0.97 (m, 4H).77 3-[8-amino-6-(3,5- dimethylisoxazol-4-yl)imidazo[1,2-a]pyrazin-3-yl]- N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

497.2 ¹H NMR (400 MHz, DMSO-d₆) δ 7.84-7.78 (m, 2H), 7.71 (s, 1H),7.66-7.56 (m, 2H), 7.27 (s, 1H), 7.19 (br s, 2H), 4.45 (d, J = 4.2 Hz,1H), 3.28-3.20 (m, 1H), 3.01-2.78 (m, 1H), 2.46 (s, 3H), 2.28 (d, J =12.4 Hz, 6H), 1.74-1.63 (m, 2H), 1.62-1.49 (m, 2H), 1.21-0.95 (m, 4H).78 3-{8-amino-6-[1-(1-cyano-1- methylethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-3-yl}- N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

535.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (s, 1H), 7.99 (s, 1H), 7.85 (d, J= 8.0 Hz, 1H), 7.77 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H),7.55 (s, 1H), 7.13 (s, 2H), 4.47 (br s, 1H), 3.28-3.22 (m, 1 H),3.03-2.84 (m, 1H), 2.24 (s, 3H), 1.96 (s, 6H), 1.73-1.57 (m, 4H), 1.12(dq, J = 35.0, 11.7, 9.9 Hz, 4H). 79 4-[8-Amino-3-(5-{[(trans-4-hydroxycyclohexyl)amino] sulfonyl}-2- methylphenyl)imidazo[1,2-a]pyrazin-6-yl]-3-fluoro-N,N- dimethylbenzamide trifluoroacetate

567.2 80 3-{8-Amino-6-[1-methyl-3- (trifluoromethyl)-1H-pyrazol-5-yl]imidazo[1,2-a]pyrazin-3-yl}- N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

550.2 81 3-[8-Amino-6-(3-fluoropyridin- 4-yl)imidazo[1,2-a]pyrazin-3-yl]-N-(trans-4- hydroxycyclohexyl)-4- methylbenzenesulfonamide

497.1 82 3-(8-Amino-6-(2-fluoro-4-(1- hydroxyethyl)phenyl)imidazo[1,2-a]pyrazin-3-yl)-N-(trans-4- hydroxycyclohexyl)-4-methylbenzenesulfonamide

540.1

Example 36.3-[6-(2-Fluorophenyl)-8-(methylamino)imidazo[1,2-a]pyrazin-3-yl]-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamidetrifluoroacetate

Step 1. 6-Bromo-3-iodo-N-methylimidazo[1,2-a]pyrazin-8-amine

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 16, Step 2 substitutingmethylamine (40% w/w in water) for conc. NH₄OH (aq). LCMS for C₇H₇BrIN₄(M+H)⁺: calculated m/z=352.9, 354.9; found 352.9, 354.9.

Step 2.3-[6-(2-Fluorophenyl)-8-(methylamino)imidazo[1,2-a]pyrazin-3-yl]-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamidetrifluoroacetate

A mixture of 6-bromo-3-iodo-N-methylimidazo[1,2-a]pyrazin-8-amine (7.6mg, 0.022 mmol),N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide(Example 1, Step 2, 10 mg, 0.02 mmol),tetrakis(triphenylphosphine)palladium(0) (2 mg, 0.002 mmol), ethanol(0.5 mL), and 2.0 M Na₂CO₃ in water (22 μL, 0.043 mmol) was degassed for5 min with N₂. The reaction mixture was then heated in a microwavereactor at 130° C. for 30 min. The reaction mixture was diluted withMeOH and filtered through a plug of Celite. The filtrate wasconcentrated to afford the crude intermediate.

A 1-dram vial was charged with the crude intermediate,(2-fluorophenyl)boronic acid (9 mg, 0.06 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (4 mg, 0.004 mmol). THF (0.4 mL) and 1.0 M K₂CO₃ inwater (56 μL, 0.056 mmol) were added. The reaction mixture was degassedwith N₂ briefly and then heated at 80° C. overnight. The reactionmixture was diluted with MeOH and filtered through a plug of Na₂SO₄ andCelite. Purification via preparative HPLC on a C-18 column (pH 10,36-56% MeCN/0.1% NH₄OH (aq) over 5 min, 60 mL/min) and then subsequentpurification via preparative HPLC on a C-18 column (pH 2, 31-42%MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded the title compound asa white solid (4.2 mg, 30%). ¹H NMR (400 MHz, d₆-DMSO) δ 8.20 (t, J=7.3Hz, 1H), 7.93-7.83 (br m, 2H), 7.82 (s, 1H), 7.73 (s, 1H), 7.70-7.62 (m,2H), 7.60 (s, 1H), 7.44-7.36 (m, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.23 (dd,J=12.0, 8.2 Hz, 1H), 3.34-3.20 (m, 1H), 3.08 (d, J=2.2 Hz, 3H),3.00-2.87 (m, 1H), 1.68 (apparent d, J=10.8 Hz, 2H), 1.59 (apparent d,J=11.6 Hz, 2H), 1.31-0.93 (m, 4H). LCMS for C₂₆H₂₉FN₅O₃S (M+H)⁺:calculated m/z=510.2; found 510.1.

Example 37.3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 16, substituting8-bromo-6-methylimidazo[1,2-a]pyrazine (Frontier, B12886) for6,8-dibromoimidazo[1,2-a]pyrazine. ¹H NMR (600 MHz, d₆-DMSO) δ 7.83 (dd,J=8.0, 2.0 Hz, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.64 (d, J=8.1 Hz, 2H), 7.60(s, 1H), 7.00 (d, J=1.0 Hz, 1H), 6.98 (br s, 2H), 4.47 (d, J=4.2 Hz,1H), 3.36-3.22 (m, 1H), 3.00-2.87 (m, 1H), 2.23 (s, 3H), 2.15 (d, J=0.8Hz, 3H), 1.75-1.68 (m, 2H), 1.65-1.57 (m, 2H), 1.22-1.13 (m, 2H),1.13-1.04 (m, 2H). LCMS for C₂₀H₂₆N₅O₃S (M+H)⁺: calculated m/z=416.2;found 416.2.

Example 38.3-(8-Amino-6-ethylimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

Step 1.3-(8-Amino-6-vinylimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

A microwave vial was charged with3-(8-amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide(Example 16, 21 mg, 0.044 mmol), potassium vinyltrifluoroborate (17 mg,0.12 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (6 mg, 0.007 mmol). THF (0.57 mL) and 1.0 M K₂CO₃in water (0.12 mL, 0.12 mmol) were added. The reaction mixture wasdegassed with N₂ for 5 min and subsequently heated to 80° C. for 4 h.The reaction mixture was diluted with MeOH and filtered through a plugof Na₂SO₄ and Celite. The filtrate was concentrated. Purification viasilica gel chromatography (1-10% MeOH in DCM) afforded the titlecompound as a light brown solid (17 mg, 91%). LCMS for C₂₁H₂₆N₅O₃S(M+H)⁺: calculated m/z=428.2; found 428.3.

Step 2.3-(8-Amino-6-ethylimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

To a solution of3-(8-amino-6-vinylimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide(8 mg, 0.02 mmol) in ethanol (4 mL) under N₂ was added wet 10% Pd/C (8mg, ˜50% H₂O) [Sigma-Aldrich, 330108]. The reaction mixture was thenplaced under an atm of H₂ and stirred for 1 h. The reaction mixture wasfiltered through Celite, the Celite plug was rinsed with MeOH, and thefiltrate was concentrated. Purification via preparative HPLC on a C-18column (pH 10, 23-40% MeCN/0.1% NH₄OH (aq) over 5 min, 60 mL/min)afforded the title compound as a white solid (5 mg, 60%). ¹H NMR (600MHz, d₆-DMSO) δ 7.83 (dd, J=8.0, 2.0 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H),7.64 (d, J=8.1 Hz, 1H), 7.61 (s, 1H), 6.98 (s, 2H), 6.97 (s, 1H), 4.47(s, 1H), 3.38-3.24 (m, 1H), 2.99-2.87 (m, 1H), 2.45 (q, J=7.4 Hz, 2H),2.23 (s, 3H), 1.75-1.66 (m, 2H), 1.65-1.57 (m, 2H), 1.23-1.03 (m, 7H).LCMS for C₂₁H₂₈N₅O₃S (M+H)⁺: calculated m/z=430.2; found 430.2.

Example 39.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 13, substituting7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine (Synthonix, A8092) for3-bromoimidazo[1,2-a]pyrazin-8-amine. ¹H NMR (600 MHz, d₆-DMSO) δ 8.28(apparent d, J=48.1 Hz, 2H), 8.06 (s, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.79(s, 1H), 7.78 (dd, J=8.0, 2.0 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 4.47 (s,1H), 3.39-3.23 (m, 1H), 3.01-2.85 (m, 1H), 2.33 (s, 3H), 1.75-1.67 (m,2H), 1.67-1.59 (m, 2H), 1.22-1.12 (m, 2H), 1.12-1.02 (m, 2H). LCMS forC₁₈H₂₃N₆O₃S (M+H)⁺: calculated m/z=403.2; found 403.2.

Example 40.6-(2-Fluorophenyl)-3-[2-methyl-5-(methylsulfonyl)phenyl]imidazo[1,2-a]pyrazin-8-aminetrifluoroacetate

Step 1.4,4,5,5-Tetramethyl-2-[2-methyl-5-(methylsulfonyl)phenyl]-1,3,2-dioxaborolane

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 1, Step 2 substituting2-bromo-1-methyl-4-(methylsulfonyl)benzene (Combi-Blocks, OT-1007) for3-bromo-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide. ¹H NMR(400 MHz, CDCl₃) δ 8.31 (d, J=2.0 Hz, 1H), 7.86 (dd, J=8.1, 2.2 Hz, 1H),7.34 (d, J=8.1 Hz, 1H), 3.04 (s, 3H), 2.62 (s, 3H), 1.35 (s, 12H). LCMSfor C₁₄H₂₂BO₄S (M+H)⁺: calculated m/z=297.1; found 297.1.

Step 2.6-(2-Fluorophenyl)-3-[2-methyl-5-(methylsulfonyl)phenyl]imidazo[1,2-a]pyrazin-8-aminetrifluoroacetate

A mixture of 6-bromo-3-iodoimidazo[1,2-a]pyrazin-8-amine (Example 16,Step 2, 10. mg, 0.030 mmol),4,4,5,5-tetramethyl-2-[2-methyl-5-(methylsulfonyl)phenyl]-1,3,2-dioxaborolane(10. mg, 0.035 mmol), tetrakis(triphenylphosphine)palladium(0) (2 mg,0.002 mmol), ethanol (0.52 mL), and 2.0 M Na₂CO₃ in water (30 μL, 0.059mmol) was degassed for 5 min with N₂. The reaction mixture was thenheated in a microwave reactor at 130° C. for 30 min. The reactionmixture was diluted with MeOH and filtered through a plug of Na₂SO₄ andCelite. The filtrate was concentrated to afford the crude intermediate.

A 1-dram vial was charged with the crude intermediate,(2-fluorophenyl)boronic acid (12 mg, 0.090 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (5 mg, 0.006 mmol). THF (0.5 mL) and then 1.0 MK₂CO₃ in water (75 μL, 0.075 mmol) were added. The reaction mixture wasdegassed with N₂ for 15 min and then heated at 80° C. for 16 h. Heatingwas discontinued, and the reaction mixture was stirred for 3 days. Thereaction mixture was diluted with MeOH and filtered through a plug ofNa₂SO₄ and Celite. Purification via preparative HPLC on a C-18 column(pH 10, 29-52% MeCN/0.1% NH₄OH (aq) over 5 min, 60 mL/min) and thensubsequent purification via preparative HPLC on a C-18 column (pH 2,24-39% MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded the titlecompound as a white solid (3.3 mg, 22%). ¹H NMR (400 MHz, d₆-DMSO) δ8.06-7.91 (m, 3H), 7.81 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.65 (s, 1H),7.45-7.37 (m, 1H), 7.35-7.20 (m, 2H), 3.26 (s, 3H), 2.31 (s, 3H). LCMSfor C₂₀H₁₈FN₄O₂S (M+H)⁺: calculated m/z=397.1; found 397.2.

Examples listed in Table 3 were synthesized according to proceduresanalogous to the synthesis of Example 1, Steps 1 and 2, and Example 13.

TABLE 3

LCMS Ex. Name R = [M + H]⁺ No. ¹H NMR Spectrum 415-(8-Aminoimidazo[1,2-a]pyrazin-3- 4-Me 402.2yl)-N-(trans-4-hydroxycyclohexyl)-2- methylbenzenesulfonamide ¹H NMR(400 MHz, d₆-DMSO) δ 8.02 (d, J = 1.7 Hz, 1H), 7.83-7.73 (m, 3H), 7.68(d, J = 4.7 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 4.7 Hz, 1H),7.01 (s, 2H), 4.45 (d, J = 4.3 Hz, 1H), 3.28-3.19 (m, 1H), 3.04-2.86 (m,1H), 2.63 (s, 3H), 1.82-1.53 (m, 4H), 1.38-0.94 (m, 4H) 423-(8-Aminoimidazo[1,2-a]pyrazin-3- 2-F 406.1 yl)-4-fluoro-N-(trans-4-hydroxycyclohexyl)benzenesulfonamide ¹H NMR (400 MHz, d₆-DMSO) δ8.05-7.99 (m, 1H), 7.99-7.91 (m, 1H), 7.78 (s, 1H), 7.74 (s, 1H),7.70-7.61 (m, 1H), 7.53-7.44 (m, 1H), 7.30 (d, J = 4.7 Hz, 1H), 7.05 (s,2H), 4.46 (d, J = 4.2 Hz, 1H), 3.38-3.19 (m, 1H), 3.05-2.88 (m, 1H),1.81-1.51 (m, 4H), 1.28-0.95 (m, 4H) 435-(8-Aminoimidazo[1,2-a]pyrazin-3- 4-OMe 418.1yl)-N-(trans-4-hydroxycyclohexyl)-2- methoxybenzenesulfonamide ¹H NMR(400 MHz, d₆-DMSO) δ 7.90 (d, J = 2.2 Hz, 1H), 7.88-7.82 (m, 1H), 7.71(s, 1H), 7.62 (d, J = 4.7 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 7.34 (br s,1H), 7.28 (d, J = 4.7 Hz, 1H), 6.97 (s, 2H), 4.45 (d, J = 4.1 Hz, 1H),3.96 (s, 3H), 3.29-3.20 (m, 1H), 3.09-2.94 (m, 1H), 1.78-1.51 (m, 4H),1.34-0.96 (m, 4H) 44 3-(8-Aminoimidazo[1,2-a]pyrazin-3- 3-Me 402.2yl)-N-(trans-4-hydroxycyclohexyl)-5- methylbenzenesulfonamide ¹H NMR(400 MHz, d₆-DMSO) δ 7.82 (s, 1H), 7.79 (s, 1H), 7.77-7.71 (m, 2H),7.71-7.64 (m, 2H), 7.32 (d, J = 4.7 Hz, 1H), 7.01 (s, 2H), 4.45 (d, J =4.3 Hz, 1H), 3.28-3.20 (m, 1H), 3.05-2.84 (m, 1H), 2.48 (s, 3H),1.83-1.47 (m, 4H), 1.33-0.95 (m, 4H) 455-(8-Aminoimidazo[1,2-a]pyrazin-3- 4-F 406.1 yl)-2-fluoro-N-(trans-4-hydroxycyclohexyl)benzenesulfonamide ¹H NMR (400 MHz, d₆-DMSO) δ 8.03(s, 1H), 7.99-7.90 (m, 2H), 7.79 (s, 1H), 7.68 (d, J = 4.7 Hz, 1H),7.66-7.56 (m, 1H), 7.30 (d, J = 4.7 Hz, 1H), 7.01 (s, 2H), 4.47 (d, J =4.2 Hz, 1H), 3.29-3.20 (m, 1H), 3.16-3.01 (m, 1H), 1.82-1.54 (m, 4H),1.40-1.18 (m, 2H), 1.18-0.96 (m, 2H) 465-(8-Aminoimidazo[1,2-a]pyrazin-3- 4-Cl 422.1 yl)-2-chloro-N-(trans-4-hydroxycyclohexyl)benzenesulfonamide ¹H NMR (400 MHz, d₆-DMSO) δ 8.15(d, J = 2.1 Hz, 1H), 7.94 (s, 1H), 7.89 (dd, J = 8.3, 2.1 Hz, 1H), 7.85(s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 4.7 Hz, 1H), 7.32 (d, J= 4.7 Hz, 1H), 7.03 (s, 2H), 4.46 (d, J = 4.0 Hz, 1H), 3.33-3.21 (m,1H), 3.14-2.96 (m, 1H), 1.84-1.53 (m, 4H), 1.42-0.98 (m, 4H) 835-(8-aminoimidazo[1,2-a]pyrazin-3-yl)- 2-Me, 432.1N-(trans-4-hydroxycyclohexyl)-2- 4-OMemethoxy-4-methylbenzenesulfonamide ¹H NMR (400 MHz, DMSO-d₆) δ 7.62 (s,1H), 7.59 (s, 1H), 7.36-7.18 (m, 3H), 7.13 (d, J = 4.6 Hz, 1H), 6.96 (s,2H), 4.45 (d, J = 4.2 Hz, 1H), 3.96 (s, 3H), 3.07-2.87 (m, 1H), 2.19 (s,3H), 1.78-1.65 (m, 2H), 1.65-1.48 (m, 2H), 1.33-1.15 (m, 2H), 1.15-0.93(m, 2H).

Compounds in the following tables were prepared by Method A (defaultmethod) or Method B as indicated (See footnote or separate column).Method A: Sulfonamide formation precedes Suzuki coupling (e.g., Example1, Steps 1 and 2; Example 13); Method B: Sulfonamide formationsubsequent to Suzuki coupling (e.g., Example 250). The sulfonamideformation can be executed via Schotten-Baumann conditions (e.g., Example251, Step 4) and/or using base (e.g. triethylamine or Hunig's base) inpolar aprotic solvent (e.g. DMF or DMA) (as in Example 250, Step 5). Forinstance, Examples listed in Table 4 were synthesized according toprocedures analogous to the synthesis of Example 1, Step 1 and 2, andExample 13. The data are listed in Table 4.

TABLE 4

LCMS Ex. Name —N(R)₂ [M + H]⁺ No. ¹H NMR Spectrum 473-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-N-cyclopropyl-4-methylbenzenesulfonamide

344.1 ¹H NMR (d₆-DMSO) δ: 7.99 (s, 1H), 7.96 (d, J = 2.7 Hz, 1H) 7.89(dd, J = 8.1, 2.0 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 8.2Hz, 1H), 7.41 (d, J = 5.7 Hz, 1H), 7.27 (d, J = 5.7 Hz, 1H), 2.26 (s,3H), 2.19-2.13 (m, 1H), 0.53-0.45 (m, 2H), 0.43-0.37 (m, 2H) 483-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-4-methyl-N-(tetrahydrofuran-3-ylmethyl)benzenesulfonamide

388.1 ¹H NMR (d₆-DMSO) δ: 7.94 (s, 1H), 7.90 (dd, J = 8.1, 2.0 Hz, 1H),7.85 (d, J = 7.2 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 8.2 Hz,1H), 7.35 (d, J = 5.5 Hz, 1H), 7.28 (d, J = 5.5 Hz, 1H), 3.75-3.68 (m,2H), 3.26-3.18 (m, 4H), 2.25 (s, 3H), 1.56-1.50 (m, 1H), 1.41-1.31 (m,2H) 49 3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-4-methyl-N-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide

388.1 50 3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-N-(3-hydroxypropyl)-4-methylbenzenesulfonamide

362.1 51 1-{[3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl]sulfonyl}piperidin-4-ol

388.1 ¹H NMR (d₆-DMSO) δ: 7.76 (dd, J = 8.1, 2.0 Hz, 1H), 7.70 (d, J =8.1 Hz, 1H), 7.68 (s, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 4.7Hz, 1H), 7.21 (d, J = 4.7 Hz, 1H), 7.00 (s, 2H), 4.68 (s, 1H), 3.59-3.49(m, 1H), 3.23-3.11 (m, 2H), 2.80-2.67 (m, 2H), 2.25 (s, 3H), 1.78-1.68(m, 2H), 1.48-1.35 (m, 2H) 523-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexyl)-N,4- dimethylbenzenesulfonamide

416.1 ¹H NMR (d₆-DMSO) δ: 7.82 (dd, J = 8.1, 2.0 Hz, 1H), 7.71 (d, J =2.0 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.65 (s, 1H), 7.23 (d, J = 4.7Hz, 1H), 7.13 (d, J = 4.7 Hz, 1H), 7.01 (s, 2H), 4.50 (m, 1H), 3.70-3.58(m, 1H), 3.28-3.22 (m, 1H), 2.66 (s, 3H), 2.22 (s, 3H), 1.81-1.70 (m,2H), 1.49-1.37 (m, 2H), 1.27 (d, J = 11.9 Hz, 2H), 1.22-1.10 (m, 2H) 533-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-methoxycyclohexyl)-4-methylbenzenesulfonamide

416.1 54 3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-3-hydroxycyclobutyl)-4-methylbenzenesulfonamide

374.1 55 tert-Butyl [trans-4-({[3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-4- methylphenyl]sulfonyl}amino)cyclohexyl]carbamate

501.1 56 3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-N-[trans-3-(hydroxymethyl)cyclobutyl]-4- methylbenzenesulfonamide

388.1 57 3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-N-[(3S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]-4- methylbenzenesulfonamide

418.1 84 3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-N-(4,4-difluorocyclohexyl)-4-methylbenzenesulfonamide

422.1 85 3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxy-4-methylcyclohexyl)-4- methylbenzenesulfonamide

416.1 86 3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-N-((1-(cyclopropanecarbonyl)piperidin-4-yl)methyl)-4- methylbenzenesulfonamide

469.1 ^(‡) or ^(B) denotes that the compound named was prepared usingMethod B (Scheme X).

Example 58.N-(trans-4-Aminocyclohexyl)-3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylbenzenesulfonamide

tert-Butyl[trans-4-({[3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl]sulfonyl}amino)cyclohexyl]carbamate(Example 55) was treated with TFA/DCM for 15 min. The reaction mixturewas concentrated. Purification via preparative HPLC on a C-18 column (pH10, 15-33% 0.1% MeCN/NH₄OH (aq) over 5 min, 60 mL/min) afforded thetitle compound (1.2 mg). LCMS for C₁₉H₂₅N₆O₂S (M+H)⁺: calculatedm/z=401.2; found 401.3.

Example 59.N—[trans-4-({[3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl]sulfonyl}amino)cyclohexyl]acetamide

Step 1.N-(trans-4-Aminocyclohexyl)-3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylbenzenesulfonamidehydrochloride

tert-Butyl[trans-4-({[3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl]sulfonyl}amino)cyclohexyl]carbamate(18.9 mg, 0.037 mmol) was stirred with 4.0 M hydrogen chloride in1,4-dioxane (1.0 mL, 4.0 mmol) at room temperature for 15 min.Evaporation gave the title compound (17.0 mg). LCMS for C₁₉H₂₅N₆O₂S(M+H)⁺: calculated m/z=401.2; found 401.1.

Step 2.N—[trans-4-({[3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl]sulfonyl}amino)cyclohexyl]acetamide

To a solution ofN-(trans-4-aminocyclohexyl)-3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylbenzenesulfonamidehydrochloride (8.5 mg, 0.019 mmol) in methylene chloride (0.64 mL) wasadded triethylamine (16.3 μL, 0.117 mmol) and acetyl chloride (2.1 μL,0.029 mmol). The reaction mixture was stirred for 2 min and diluted withMeOH. Purification via preparative HPLC on a C-18 column (pH 10, 17-37%0.1% MeCN/NH₄OH (aq) over 5 min, 60 mL/min) afforded the title compoundas a white residue (3.4 mg). LCMS for C₂₁H₂₇N₆O₃S (M+H)⁺: calculatedm/z=443.2; found 443.1.

Examples 60 to 72 were synthesized according to procedures analogous tothe synthesis of Example 1, Steps 1 and 2, and Example 39. The data arelisted in Table 5. Examples 215 to 248 were made from the coupling ofthe corresponding amine and3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzene-1-sulfonylchloride (i.e., Method B). Example 174 was prepared using Method B withtert-butyl (S)-2-(hydroxymethyl)piperazine-1-carboxylate. The BOCintermediate (S)-tert-butyl4-(3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylphenylsulfonyl)-2-(hydroxymethyl)piperazine-1-carboxylatewas then stirred at room temperature for 24 h with 2.0 M phosgene intoluene to prepare Example 174.

TABLE 5

LCMS Name N(R)₂ [M + H]⁺ Ex. No. ¹H NMR  603-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-[trans-3-(hydroxymethyl)cyclobutyl]-4-methylbenzenesulfonamide

389.1 ¹H NMR (400 MHz, CD₃OD) δ 8.08 (s, 1H), 7.95 (d, J = 1.7 Hz, 1H),7.89-7.81 (m, 1H), 7.73 (s, 1H), 7.58 (d, J = 8.1 Hz, 1H), 3.88 (m, 1H),3.51 (d, J = 6.9 Hz, 2H), 2.37 (s, 3H), 2.23 (s, 1H), 2.04-1.93 (m, 4H). 61 3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-[cis-3-(hydroxymethyl)cyclobutyl]-4-methylbenzenesulfonamide

389.0 ¹H NMR (400 MHz, CD₃OD) δ 8.07 (s, 1H), 7.96 (d, J = 1.9 Hz, 1H),7.89-7.83 (m, 1H), 7.73 (s, 1H), 7.58 (d, J = 8.1 Hz, 1H), 3.76-3.61 (m,1H), 3.42 (d, J = 6.0 Hz, 2H), 2.37 (s, 3H), 2.19 (m, 2H), 2.00 (m, 1H),1.64-1.51 (m, 2H).  623-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-[(3S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]-4- methylbenzenesulfonamide

419.1 ¹H NMR (400 MHz, CD₃OD) δ 8.08 (s, 1H), 8.01 (d, J = 1.9 Hz, 1H),7.89 (dd, J = 8.1, 1.9 Hz, 1H), 7.75 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H),3.92 (d, J = 10.6 Hz, 1H), 3.46 (d, J = 4.9 Hz, 2H), 3.23-3.04 (m, 3H),2.39 (s, 3H), 1.86 (s, 1H), 1.64 (d, J = 12.6 Hz, 1H), 1.48-1.23 (m,2H).  63 3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(cis-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

403.1 ¹H NMR (400 MHz, CD₃OD) δ 8.06 (s, 1H), 8.00 (d, J = 1.8 Hz, 1H),7.89 (dd, J = 8.1, 1.9 Hz, 1H), 7.73 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H),3.75 (m, 1H), 3.22-3.13 (m, 1H), 2.38 (s, 3H), 1.74-1.60 (m, 4H),1.60-1.44 (m, 4H).  64 3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-cyclopropyl-4-methylbenzenesulfonamide

345.1  65 3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3-hydroxypropyl)-4-methylbenzenesulfonamide

363.1  66 1-{[3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl]sulfonyl}piperidin-4-ol

389.1  67 3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-(tetrahydrofuran-3-ylmethyl)benzenesulfonamide

389.1  68 3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide

389.1 ¹H NMR (d₆-DMSO) δ 8.05 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.78(s, 1H), 7.76 (dd, J = 8.0, 2.0 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H),3.68-3.60 (m, 2H), 3.57-3.50 (m, 1H), 3.40-3.35 (m, 1H), 2.76-2.70 (m,2H), 2.31 (s, 3H), 2.30-2.25 (m, 1H), 1.90-1.81 (m, 1H), 1.51- 1.41 (m,1H)  69 3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(trans-4-hydroxycyclohexyl)-N,4-dimethylbenzenesulfonamide

417.1  70 3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(trans-4-methoxycyclohexyl)-4-methylbenzenesulfonamide

417.1  71 3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(trans-3-hydroxycyclobutyl)-4-methylbenzenesulfonamide

375.1  72 tert-Butyl [trans-4-({[3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl]sulfonyl}amino)cyclohexyl]carbamate

502.1  87 3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1r,3r)-3-cyano-3-methylcyclobutyl)-4-methylbenzenesulfonamide trifluoroacetatesalt

398.0 ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (s, 1H), 8.26 (s, 1H), 8.14-8.06(m, 2H), 7.93 (d, J = 1.3 Hz, 1H), 7.83 (s, 1H), 7.78 (dd, J = 8.1, 1.5Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 3.88-3.77 (m, 1H), 2.66-2.55 (m, 2H),2.36 (s, 3H), 1.98-1.86 (m, 2H), 1.37 (s, 3H)  88‡ Methyl3-(3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylphenylsulfonamido)bicyclo[1.1.1]pentane-1- carboxylatetrifluoroacetate salt

429.1 ¹H NMR (400 MHz, CD₃OD) δ 8.13 (s, 1H), 8.01 (d, J = 1.9 Hz, 1H),7.88 (dd, J = 8.1, 1.9 Hz, 1H), 7.81 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H),3.66 (s, 3H), 2.42 (s, 3H), 2.12 (s, 6H)  893-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1r,3r)-3-cyanocyclobutyl)-4-methylbenzenesulfonamide trifluoroacetate salt

384.1 ¹H NMR (500 MHz, DMSO-d₆) δ 8.45 (s, 1H), 8.34 (s, 1H), 8.18 (d, J= 8.1 Hz, 1H), 8.12 (s, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.84 (s, 1H),7.78 (dd, J = 8.1, 2.0 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 4.01-3.91 (m,1H), 3.22-3.10 (m, 1H), 2.43-2.35 (m, 2H), 2.35 (s, 3H), 2.25-2.15 (m,2H).  90‡ 3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.2.1]heptan-1-yl)-4- methylbenzenesulfonamidetrifluoroacetate salt

424.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (s, 1H), 8.29 (s, 1H), 8.24 (s,1H), 8.09 (s, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.83 (s, 1H), 7.81 (dd, J =8.1, 2.0 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 2.36 (s, 3H), 1.98-1.85 (m,2H), 1.82 (s, 2H), 1.80-1.64 (m, 4H), 1.56-1.44 (m, 2H)  91‡3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(3-(cyanomethyl)bicyclo[1.1.1]pentan-1-yl)-4- methylbenzenesulfonamidetrifluoroacetate salt

410.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (s, 1H), 8.38 (s, 1H), 8.28 (s,1H), 8.10 (s, 1H), 7.92 (d, J = 1.7 Hz, 1H), 7.82 (s, 1H), 7.79 (dd, J =8.1, 1.8 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 2.81 (s, 2H), 2.35 (s, 3H),1.74 (s, 6H)  92‡N-(3-((1H-pyrazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4- methylbenzenesulfonamidetrifluoroacetate salt

451.3 ¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (s, 1H), 8.45 (s, 1H), 8.34 (s,1H), 8.07 (s, 1H), 7.88 (d, J = 1.9 Hz, 1H), 7.80 (s, 1H), 7.75 (dd, J =8.1, 1.9 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H),7.38 (d, J = 1.7 Hz, 1H), 6.19 (t, J = 2.0 Hz, 1H), 4.21 (s, 2H), 2.34(s, 3H), 1.61 (s, 6H)  93‡3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(3-(2-hydroxypropan-2-yl)bicyclo[1.1.1]pentan-1-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

429.1 ¹H NMR (400 MHz, CD₃OD) δ 8.13 (s, 1H), 7.99 (d, J = 1.8 Hz, 1H),7.88 (dd, J = 8.1, 1.9 Hz, 1H), 7.80 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H),2.39 (s, 3H), 1.74 (s, 6H), 1.10 (s, 6H)  94‡3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(3-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[1.1.1]pentan-1-yl)benzenesulfonamide trifluoroacetate salt

453.1 ¹H NMR (400 MHz, CD₃OD) δ 8.12 (s, 1H), 8.05 (d, J = 1.6 Hz, 1H),7.90 (dd, J = 8.1, 1.6 Hz, 1H), 7.81 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H),2.42 (s, 3H), 2.36 (s, 6H), 2.33 (s, 3H)  95‡N-(3-Acetylbicyclo[1.1.1]pentan-1-yl)-3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4- methylbenzenesulfonamidetrifluoroacetate salt

413.2 ¹H NMR (500 MHz, CD₃OD) δ 8.08 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H),7.88 (dd, J = 8.1, 2.0 Hz, 1H), 7.76 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H),2.40 (s, 3H), 2.11 (s, 6H), 2.10 (s, 3H)  96‡3-(3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylphenylsulfonamido)-N,N-dimethylbicyclo[1.1.1]pentane-1-carboxamide trifluoroacetate salt

442.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.42 (s, 1H), 8.31 (s,1H), 8.09 (s, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.83 (s, 1H), 7.80 (dd, J =8.1, 1.9 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 2.92 (s, 3H), 2.75 (s, 3H),2.35 (s, 3H), 2.04 (s, 6H)  97‡3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1- yl)benzenesulfonamidetrifluoroacetate salt

439.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.91 (s, 1H), 8.41 (s, 1H), 8.30 (s,1H), 8.03 (s, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7.84 (s, 1H), 7.81 (dd, J =8.1, 2.0 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 2.37 (s, 3H), 2.03 (s, 6H) 98‡ 3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)-4- methylbenzenesulfonamidetrifluoroacetate salt

389.1 ¹H NMR (400 MHz, CD₃OD) δ 8.10 (s, 1H), 7.99 (d, J = 1.8 Hz, 1H),7.87 (dd, J = 8.1, 1.8 Hz, 1H), 7.79 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H),2.40 (s, 3H), 2.14 (d, J = 2.0 Hz, 6H)  99‡N-(3-(1H-tetrazol-5-yl)bicyclo[1.1.1]pentan-1-yl)-3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4- methylbenzenesulfonamidetrifluoroacetate salt

439.1 ¹H NMR (400 MHz, CD₃OD) δ 8.10 (s, 1H), 8.04 (d, J = 1.6 Hz, 1H),7.92 (dd, J = 8.1, 1.7 Hz, 1H), 7.80 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H),2.41 (s, 3H), 2.36 (s, 6H) 1003-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(2-methyltetrahydrofuran-3-yl)benzenesulfonamide trifluoroacetate salt(mixture of diastereomers prepared)

389.1 101 3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1-cyanocyclopropyl)methyl)-4-methylbenzenesulfonamide trifluoroacetatesalt

384.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (s, 1H), 8.32 (s, 1H), 8.24 (t, J= 6.4 Hz, 1H), 8.10 (s, 1H), 7.91 (d, J = 1.7 Hz, 1H), 7.85-7.69 (m,2H), 7.61 (d, J = 8.2 Hz, 1H), 2.95 (d, J = 6.4 Hz, 2H), 2.32 (s, 3H),1.22-1.09 (m, 2H), 1.06-0.91 (m, 2H) 1023-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1-cyanocyclobutyl)methyl)-4-methylbenzenesulfonamide trifluoroacetate salt

398.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (s, 1H), 8.32 (s, 1H), 8.22 (t, J= 6.7 Hz, 1H), 8.10 (s, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.86-7.80 (m,2H), 7.63 (d, J = 8.1 Hz, 1H), 3.14 (d, J = 6.7 Hz, 2H), 2.38-2.27 (m,2H), 2.34 (s, 3H), 2.24-2.10 (m, 2H), 2.07-1.84 (m, 2H) 103N-(1-Acetylazetidin-3-yl)-3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-methylbenzenesulfonamide trifluoroacetate salt

402.1 104 3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(oxetan-3-yl)benzenesulfonamide

361.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (d, J = 8.1 Hz, 1H), 8.38 (s,1H), 8.28 (s, 1H), 8.10 (s, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.82 (s, 1H),7.77 (dd, J = 8.1, 1.9 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 4.54 (t, J =6.7 Hz, 2H), 4.41 (dq, J = 14.4, 7.6, 7.1 Hz, 1H), 4.28 (t, J = 6.3 Hz,2H), 2.33 (s, 3H) 105‡3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-4- methylbenzenesulfonamidetrifluoroacetate salt

401.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (s, 1H), 8.39 (s, 1H), 8.29 (s,1H), 8.09 (s, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.80 (s, 1H), 7.78 (dd, J =8.1, 1.9 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 3.35 (s, 2H), 2.34 (s, 3H),1.60 (s, 6H) 106‡ 3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-4-methylbenzenesulfonamide trifluoroacetatesalt

371.1 ¹H NMR (400 MHz, CD₃OD) δ 8.11 (s, 1H), 7.98 (d, J = 1.9 Hz, 1H),7.88 (dd, J = 8.1, 2.0 Hz, 1H), 7.79 (s, 1H), 7.60 (d, J = 8.1 Hz, 1H),2.39 (s, 3H), 2.31 (s, 1H), 1.86 (s, 6H). 107‡3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-4- methylbenzenesulfonamidetrifluoroacetate salt

415.2 ¹H NMR (400 MHz, CD₃OD) δ 8.11 (s, 1H), 8.00 (d, J = 1.5 Hz, 1H),7.90 (d, J = 8.2, 1.6 Hz, 1H), 7.78 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H),3.54 (s, 2H), 2.38 (s, 3H), 1.86-1.72 (m, 2H), 1.64-1.53 (m, 2H),1.53-1.43 (m, 2H), 1.27-1.18 (m, 2H) 108‡3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-(cyanomethyl)bicyclo[2.1.1]hexan-1-yl)-4- methylbenzenesulfonamidetrifluoroacetate salt

424.1 ¹H NMR (400 MHz, CD₃OD) δ 8.13 (s, 1H), 8.01 (d, J = 1.8 Hz, 1H),7.90 (dd, J = 8.1, 1.9 Hz, 1H), 7.80 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H),2.66 (s, 2H), 2.39 (s, 3H), 1.89-1.80 (m, 2H), 1.67-1.61 (m, 2H),1.61-1.53 (m, 2H), 1.43-1.31 (m, 2H) 109‡4-(3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-methylphenylsulfonamido)bicyclo[2.1.1]hexane-1- carboxylic acid

429.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (s, 1H), 8.36 (s, 1H), 8.26 (s,1H), 8.07 (s, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.83-7.77 (m, 2H), 7.61 (d,J = 8.2 Hz, 1H), 2.35 (s, 3H), 1.81-1.62 (m, 6H), 1.43-1.30 (m, 2H) 110‡4-(3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-methylphenylsulfonamido)bicyclo[2.1.1]hexane-1- carboxamidetrifluoroacetate salt

428.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (s, 1H), 8.40 (s, 1H), 8.30 (s,1H), 8.09 (s, 1H), 7.95 (d, J =1.8 Hz, 1H), 7.83-7.78 (m, 2H), 7.60 (d,J = 8.2 Hz, 1H), 7.06 (s, 1H), 6.84 (s, 1H), 2.35 (s, 3H), 1.74-1.57 (m,6H), 1.39-1.29 (m, 2H) 111‡3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(3-(oxazol-5-yl)bicyclo[1.1.1]pentan-1- yl)benzenesulfonamidetrifluoroacetate salt

438.1 ¹H NMR (400 MHz, CD₃OD) δ 8.08 (s, 1H), 8.05 (s, 1H), 8.03 (d, J =2.0 Hz, 1H), 7.90 (dd, J = 8.1, 1.9 Hz, 1H), 7.76 (s, 1H), 7.62 (d, J =8.1 Hz, 1H), 6.88 (s, 1H), 2.41 (s, 3H), 2.20 (s, 6H) 112‡N-(3-((1H-Imidazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

451.1 ¹H NMR (400 MHz, DMSO-d₆) δ 9.07-8.98 (m, 1H), 8.68 (s, 1H), 8.38(s, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.80 (s,1H), 7.76 (dd, J = 8.1, 2.0 Hz, 1H), 7.68- 7.65 (m, 1H), 7.65-7.63 (m,1H), 7.61 (d, J = 8.2 Hz, 1H), 4.35 (s, 2H), 2.34 (s, 3H), 1.68 (s, 6H)113‡ N-(3-((1H-1,2,4-triazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-3-(4-aminoimidazol[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

452.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.43 (s, 1H), 8.40 (s,1H), 8.30 (s, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 7.89 (d, J = 1.8 Hz, 1H),7.79 (s, 1H), 7.75 (dd, J = 8.1, 1.9 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H),4.31 (s, 2H), 2.34 (s, 3H), 1.64 (s, 6H) 114‡3-(4-Aminoimidazol[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(3-(thiazol-2-yl)bicyclo[1.1.1]pentan-1- yl)benzenesulfonamidetrifluoroacetate salt

454.1 ¹H NMR (400 MHz, CD₃OD) δ 8.12 (s, 1H), 8.05 (d, J = 1.9 Hz, 1H),7.92 (dd, J = 8.1, 2.0 Hz, 1H), 7.83 (s, 1H), 7.71 (d, J = 3.3 Hz, 1H),7.64 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 3.3 Hz, 1H), 2.41 (s, 3H), 2.30(s, 6H) 115‡ Methyl 3-(3-(4-aminoimidazol[1,2-f][1,2,4]triazin-7-yl)-4-methylphenylsulfonamido)bicyclo[1.1.1]pentan-1- ylcarbamatetrifluoroacetate salt

444.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (s, 1H), 8.41 (s, 1H), 8.31 (s,1H), 8.11 (s, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.82 (s, 1H), 7.78 (dd, J =8.0, 1.9 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 3.47 (s, 3H), 2.35 (s, 3H),1.90 (s, 6H) 116‡3-(4-Aminoimidazol[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(3-morpholinobicyclo[1.1.1]pentan-1- yl)benzenesulfonamidetrifluoroacetate salt

456.2 ¹H NMR (400 MHz, CD₃OD) δ 8.09 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H),7.89 (dd, J = 8.1, 2.0 Hz, 1H), 7.76 (s, 1H), 7.63 (d, J = 8.1 Hz, 1H),3.97-3.71 (m, 4H), 3.23-2.94 (m, 4H), 2.40 (s, 3H), 2.19 (s, 6H) 117‡3-(4-Aminoimidazol[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(3-methylbicyclo[1.1.1]pentan-1-yl)benzenesulfonamide

385.2 ¹H NMR (400 MHz, DMSO-d₆) δ 7.25 (s, 1H), 7.15 (s, 1H), 7.05 (d, J= 7.8 Hz, 1H), 6.92 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 1.57 (s, 3H),0.89 (s, 6H), 0.34 (s, 3H) 118‡N-(3-aminobicyclo[1.1.1]pentan-1-yl)-3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N,4- dimethylbenzenesulfonamidetrifluoroacetate salt

400.1 ¹H NMR (600 MHz, CD₃OD) δ 8.09 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H),7.85 (dd, J = 8.1, 2.1 Hz, 1H), 7.78 (s, 1H), 7.66 (d, J = 8.2 Hz, 1H),2.93 (s, 3H), 2.43 (s, 3H), 2.29 (s, 6H) 1195-{[3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl]sulfonyl}-5-azaspiro[2.5]octan-8-ol

415.2 120 8-{[3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl]sulfonyl}-8-azabicyclo[3.2.1]octan-3-ol

415.2 121 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}-4-methylbenzenesulfonamide

433.3 122 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4,4-difluorocyclohexyl)-4-methylbenzenesulfonamide

423.1 123 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]-4-methylbenzenesulfonamide

391.1 124 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-[cis-4-hydroxy-4-(trifluoromethyl)cyclohexyl]-4- methylbenzenesulfonamide

471.1 125 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-[trans-4-(1-hydroxy-1-methylethyl)cyclohexyl]-4- methylbenzenesulfonamide

445.2 126 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-[3,3-bis(hydroxymethyl)cyclobutyl]-4- methylbenzenesulfonamide

419.1 127 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(trans-4-hydroxy-1-methylcyclohexyl)-4-methylbenzenesulfonamide

417.1 128 (1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)azetidin-3-yl)methanol

375.1 129 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(2-(1,1-dioxidothiomorpholino)ethyl)-4-methylbenzenesulfonamide

466.1 130 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((4,4-difluorocyclohexyl)methyl)-4-methylbenzenesulfonamide

437.1 131 7-(5-((3-fluoroazetidin-1-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

363.1 132 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3,3-difluorocyclobutyl)-4-methylbenzenesulfonamide

395.0 133 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1S,4S)-4-hydroxy-4-methylcyclohexyl)-4-methylbenzenesulfonamide

417.2 134 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-4- methylbenzenesulfonamide

421.2 135 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1,1-dioxidotetrahydrothiophen-3-yl)methyl)-4- methylbenzenesulfonamide

437.2 136 3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-N-((1-(cyclopropanecarbonyl)piperidin-4-yl)methyl)-4- methylbenzenesulfonamide

469.1 137 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(2-hydrocyclohexyl)-4-methylbenzenesulfonamide

403.2 138 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-(2-(2-oxopyrrolidin-1-yl)ethyl)benzenesulfonamide

416.2 139 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonamide

305.1 140^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1S,3S)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-4- methylbenzenesulfonamide

443.2 141^(B) 2-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-6-(trifluoromethyl)-2- azaspiro[3.3]heptan-6-ol

469.2 142^(B) 7-(5-((8-oxa-2-azaspiro[4.5]decan-2-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

429.2 143^(B) 7-(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

387.2 144^(B) 1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-3-cyclopropylazetidin-3-ol, TFA

401.1 145^(B) 2-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-2-azaspiro[3.3]heptan-6-ol, TFA

401.1 146^(B) 7-(2-methyl-5-((3-morpholinoazetidin-1-yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine, 2TFA

430.1 147^(B) (S)-7-(5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

403.2 148^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-cyclopropyl-N,4-dimethylbenzenesulfonamide

359.2 149^(B) 7-(5-((4-azaspiro[2.5]octan-4-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

399.2 150^(B) (R)-1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)pyrrolidine-3-carbonitrile

384.2 151^(B) 7-(5-(((3R,4R)-3-fluoro-4-methoxypyrrolidin-1-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4- amine

407.2 152^(B) (R)-(1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)pyrrolidin-2-yl)methanol

389.2 153^(B) 7-(2-methyl-5-((3-(oxetan-3-yl)azetidin-1-yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

401.2 154^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(2-cyanoethyl)-N,4-dimethylbenzenesulfonamide

372.2 155^(B) 7-(5-((3,5-dimethylmorpholino)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

403.2 156^(B) 7-(5-((3,3-dimethylmorpholino)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

403.2 157^(B) (1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-6-methylpiperidin-2-yl)methanol

417.2 158^(B) 7-(2-methyl-5-((2,5,5-trimethylmorpholino)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

417.2 159^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1R,3R)-3-hydroxycyclobutyl)-N,4-dimethylbenzenesulfonamide

389.2 160^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1-(hydroxymethyl)cyclopropyl)methyl)-N,4- dimethylbenzenesulfonamide

403.2 161^(B) 4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)thiomorpholine 1,1-dioxide

423.2 162^(B) 4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-3-methylthiomorpholine 1,1- dioxide

437.2 163^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N,4-dimethyl-N-(2,2,2-trifluoroethyl)benzenesulfonamide

401.2 164^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(cyclopropylmethyl)-4-methyl-N- propylbenzenesulfonamide

401.2 165^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(2-cyanoethyl)-N-cyclopentyl-4-methylbenzenesulfonamide

426.2 166^(B) (R)-(1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)piperazin-2-yl)methanol

404.0 167^(B)(3S,4S)-1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-4-(4-methylpiperazin-1- yl)pyrrolidin-3-ol

473.2 168^(B) 7-(5-((2-(3,5-dimethylisoxazol-4-yl)pyrrolidin-1-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4- amine

454.2 169^(B) 7-(2-methyl-5-((3-morpholino-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

484.2 170^(B) 7-(2-methyl-5-(((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

414.2 171^(B) 4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-1-cyclopropylpiperazin-2-one

428.2 172^(B) (R)-2-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)octahydro-4H-pyrido[1,2-a]pyrazin- 4-one

442.2 173^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(2-cyanoethyl)-N-cyclohexyl-4-methylbenzenesulfonamide

440.2 174^(B) (R)-7-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)hexahydro-3H-oxazolo[3,4- a]pyrazin-3-one

430.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (s, 1H), 8.26 (s, 1H), 8.08 (s,1H), 7.87 (m, 2H), 7.71 (m, 2H), 4.34 (s, 1H), 3.95 (m, 2H), 3.84 (m, 1H), 3.67 (m, 2H), 3.09 (m, 1H), 2.39 (s, 3H), 2.37 (m, 2H). 175^(B)3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(2-cyanoethyl)-N-(3-hydroxypropyl)-4- methylbenzenesulfonamide

416.2 176^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N,4-dimethyl-N-((3-methyloxetan-3-yl)methyl)benzenesulfonamide

403.2 177^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(methoxymethyl)cyclopropyl)-N,4- dimethylbenzenesulfonamide

403.2 178^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1-(hydroxymethyl)cyclobutyl)methyl)-N,4- dimethylbenzenesulfonamide

417.2 179^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-ethyl-4-methyl-N-((tetrahydrofuran-2- yl)methyl)benzenesulfonamide

417.2 180 3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(bicyclo[2.2.1]heptan-1-yl)-4-methylbenzenesulfonamide trifluoroacetatesalt

399.1 181 3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(bicyclo[2.2.2]octan-1-yl)-4-methylbenzenesulfonamide trifluoroacetatesalt

413.1 182 3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(quinuclidin-4-yl)benzenesulfonamide trifluoroacetate salt

414.1 183 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((3S,6R)-6-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-4- methylbenzenesulfonamide

428.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (br s, 1H), 8.23 (br s, 1H), 8.06(s, 1H), 7.94 (s, 1H), 7.87-7.74 (m, 3H), 7.60 (d, J = 7.5 Hz, 1H), 3.72(d, J = 7.5 Hz, 1H), 3.51-3.38 (m, 1H), 3.13-2.91 (m, 2H), 2.76-2.54 (m,2H), 2.34 (s, 3H), 1.83-1.55 (m, 2H), 1.47-1.17 (m, 2H). 184‡3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(trans-4-(cyanomethyl)cyclohexyl)-4-methylbenzenesulfonamide trifluoroacetate

426.3 ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (br s, 1H), 8.25 (br s, 2H), 8.06(s, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.85-7.74 (m, 2H), 7.65 (d, J = 7.2Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 2.98- 2.80 (m, 1H), 2.37 (d, J = 6.5Hz, 2H), 2.32 (s, 3H), 1.78-1.60 (m, 3H), 1.60-1.36 (m, 1H), 1.28-1.10(m, 2H), 1.08-0.88 (m, 2H). 185‡3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-4- methylbenzenesulfonamide

429.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (br s, 1H), 8.23 (br s, 1H), 8.05(s, 1H), 7.90 (s, 1H), 7.83-7.73 (m, 2H), 7.55 (d, J = 8.1 Hz, 1H), 7.46(s, 1H), 4.23 (s, 1H), 4.23 (s, 1H), 2.32 (s, 3H), 1.81- 1.58 (m, 6H),1.57-1.33 (m, 6H). 186‡3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl)-4- methylbenzenesulfonamide

443.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (br s, 1H), 8.23 (br s, 1H), 8.05(s, 1H), 7.91 (s, 1H), 7.86-7.68 (m, 2H), 7.55 (d, J = 7.8 Hz, 1H), 7.44(s, 1H), 4.41-4.15 (m, 1H), 2.93 (d, J = 4.9 Hz, 2H), 2.32 (s, 3H),1.74-1.46 (m, 6H), 1.40-1.08 (m, 6H). 187‡3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.2.2]octan-1-yl)-4- methylbenzenesulfonamide

438.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.43-8.13 (m, 2H) 8.08 (s, 1H), 7.92(s, 1H), 7.86-7.71 (m, 2H), 7.71-7.62 (m, 1H), 7.61-7.47 (m, 1H), 2.33(s, 3H), 1.96-1.76 (m, 6H), 1.76- 1.51 (m, 6H). 188‡3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-fluorobicyclo[2.2.2]octan-1-yl)-4- methylbenzenesulfonamide

431.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.44-8.11 (m, 2H), 8.06 (s, 1H), 7.92(d, J = 1.7 Hz, 1H), 7.84-7.72 (m, 2H), 7.56 (d, J = 8.2 Hz, 1H), 2.32(s, 3H), 1.89-1.77 (m, 6H), 1.77-1.63 (m, 6H). 189‡3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1-cyanocyclopropyl)-4-methylbenzenesulfonamide

370.1 ¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.36 (br s, 1H), 8.26(br s, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.85-7.74 (m, 2H), 7.64 (d, J =8.1 Hz, 1H), 2.34 (s, 3H), 1.50-1.35 (m, 2H), 1.32-1.15 (m, 2H). 190‡2-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonamido)-2-methylpropanamide trifluoroacetate

390.3 ¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (br s, 1H), 8.28 (br s, 1H), 8.07(s, 1H), 7.93 (d, J = 1.8 Hz, 1H), 7.86-7.77 (m, 2H), 7.75 (s, 1H), 7.56(d, J = 8.2 Hz, 1H), 7.05 (d, J = 18.3 Hz, 2H), 2.31 (s, 3H), 1.23 (s,6H). 191‡ 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1s,3s)-3-hydroxy-1-methylcyclobutyl)-4-methylbenzenesulfonamide

389.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (br s, 1H), 8.22 (br s, 1H), 8.06(s, 1H), 7.90 (d, J = 1.9 Hz, 1H), 7.82 (s, 1H), 7.80-7.72 (m, 2H), 7.57(d, J = 8.1 Hz, 1H), 4.95 (d, J = 5.7 Hz, 1H), 3.84 (M, 1H), 2.31 (s,3H), 2.06 (M, 2H), 1.94 (M, 2H), 1.17 (s, 3H). 192‡3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1-cyanocyclobutyl)-4-methylbenzenesulfonamide trifluoroacetate

384.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.86 (s, 1H), 8.39 (br s, 1H), 8.28(br s, 1H), 8.08 (s, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.85-7.74 (m, 2H),7.62 (d, J = 8.2 Hz, 1H), 2.47-2.38 (m, 2H), 2.38-2.26 (m, 5H),2.03-1.80 (m, 2H). 193‡8-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-3-oxa-1,8-diazaspiro[4.5]decan-2- one

444.1 194‡ 7-(5-((1-Oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

429.2 195‡ 2-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-6-methyl-2,6-diazaspiro[3.4]octan- 5-one

428.2 196‡ 1-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-4,4-difluoropiperidin-3-ol

425.2 ¹H NMR (500 MHz, DMSO-d₆) δ 8.33 (br s, 1H), 8.24 (br s, 1H), 8.07(s, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.85 (s, 1H), 7.76 (dd, J = 8.1, 2.0Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 5.93 (d, J = 5.7 Hz, 1H), 3.81 (br s,1H), 3.26-3.13 (m, 2H), 3.04-2.97 (m, 1H), 2.96-2.88 (m, 1H), 2.38 (s,3H), 2.30-2.10 (m, 1H), 2.09-1.89 (m, 1H). 197‡(S)-1-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)pyrrolidin-3-ol

375.2 198‡ 7-(5-((Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

414.2 199‡ N-(1-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)pyrrolidin-3-yl)acetamide

416.2 200‡ 1-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-3-methylpyrrolidine-3-carbonitrile

398.2 201‡ 7-(2-Methyl-5-((3-(pyridin-4-yl)pyrrolidin-1-yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

436.2 202‡ 7-(5-((1-Oxa-7-azaspiro[4.4]nonan-7-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

415.1 203‡ 7-(5-((7-Oxa-2-azaspiro[4.5]decan-2-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

429.1 204‡ 7-(5-((3-(Dimethylamino)pyrrolidin-1-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

402.1 205‡ 7-(5-((1-Oxa-6-azaspiro[3.4]octan-6-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

401.1 206‡ 7-(2-Methyl-5-((1-methyl-8-oxa-2-azaspiro[4.5]decan-2-yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

443.1 207‡ 7-(5-((8,8-Difluoro-2-azaspiro[4.5]decan-2-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

463.1 208‡ 7-(5-((7-Oxa-1-azaspiro[4.4]nonan-1-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

415.1 209‡ 7-(5-((8-Oxa-1-azaspiro[4.5]decan-1-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

429.1 210‡ 7-(5-((Hexahydropyrano[3,4-c]pyrrol-2(3H)-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

415.1 211‡ 7-(5-((cis-Hexahydro-5H-furo[2,3-c]pyrrol-5-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

401.1 212‡ (S)-(1-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-4,4-difluoropyrrolidin-2- yl)methanol

425.1 213‡ (S)-2-(1-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)pyrrolidin-2-yl)propan-2-ol

417.2 214 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide

413.2 215^(B) 7-(5-((6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4- amine

411.2 216^(B) 7-(2-methyl-5-((4-(pyridin-2-yl)piperidin-1-yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

450.2 217^(B) 1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)piperdine-4-carbonitrile

398.2 218^(B) 7-(2-methyl-5-((3-(trifluoromethyl)piperidin-1-yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

441.2 219^(B) 7-(2-methyl-5-((3-(tetrahydrofuran-3-yl)azetidin-1-yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

415.1 220^(B) 7-(5-((6-oxa-2-azaspiro[3.4]octan-2-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

401.1 221^(B) 7-(5-((-2-oxa-6-azaadamantan-6-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

427.1 222^(B) 7-(2-methyl-5-((8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)sulfonyl)phenyl)imidazo[2,1- f][1,2,4]triazin-4-amine

426.2 223^(B) 7-(5-((5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4- amine

411.1 224^(B) 7-(2-methyl-5-((3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin- 4-amine

411.2 225^(B) 7-(2-methyl-5-((2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

425.3 226^(B) N-(1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)piperidin-4-yl)acetamide

430.2 227^(B) 1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-N-methylpiperidine-4-carboxamide

430.2 228^(B) 4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-1-methylpiperazin-2-one

402.2 229^(B) 1-(4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)piperazin-1-yl)ethan-1-one

416.3 230^(B) 7-(2-methyl-5-((4-(pyrimidin-2-yl)piperazin-1-yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

452.1 231^(B) 3-(4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)piperazin-1-yl)pyrazine-2- carbonitrile

477.2 232^(B) 6-(4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)piperazin-1-yl)nicotinonitrile

476.2 233^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-(pyrazin-2-ylmethyl)benzenesulfonamide

397.1 234^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-(2,2,2-trifluoro-1-(pyridin-2-yl)ethyl)benzenesulfonamide

464.1 235^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-((6-(trifluoromethyl)pyridin-2- yl)methyl)benzenesulfonamide

464.1 236^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-((1-methyl-1H-pyrazol-5-yl)methyl)benzenesulfonamide

399.1 237^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-((5-methyl-1,2,4-oxadiazol-3- yl)methyl)benzenesulfonamide

401.1 238^(B) N-(2-amino-1-cyclopropylethyl)-3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonamide

388.3 239^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-(2-methyl-1-(pyrrolidin-1-yl)propan-2- yl)benzenesulfonamide

430.2 240^(B) 5-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carbonitrile

436.2 241^(B) 7-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-N-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide

536.2 242^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(6-(3-hydroxyazetidine-1-carbonyl)pyridin-3-yl)-4- methylbenzenesulfonamide

481.2 243^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-(1H-pyrazolo[3,4-c]pyridin-5-yl)benzenesulfonamide

422.1 244^(B) N-(5-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonamido)pyridin-2-yl)acetamide

439.2 245^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-(4-methylpyridin-3-yl)benzenesulfonamide

396.1 246^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(6-methoxy-2-methylpyridin-3-yl)-4- methylbenzenesulfonamide

426.1 247^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N,4-dimethyl-N-(pyridin-4-yl)benzenesulfonamide

396.2 248^(B) 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(2-cyanopyridin-4-yl)-4-methylbenzenesulfonamide

407.2 ‡or ^(B) denotes that the compound named was prepared using MethodB (Scheme X).

Example 73.N-(trans-4-Aminocyclohexyl)-3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylbenzenesulfonamidebis-hydrochloride

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 59, Step 1 substituting tert-butyl[trans-4-({[3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl]sulfonyl}amino)cyclohexyl]carbamate(Example 72) for tert-butyl[trans-4-({[3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl]sulfonyl}amino)cyclohexyl]carbamate.LCMS for C₁₈H₂₄N₇O₂S (M+H)⁺: calculated m/z=402.2; found 402.1.

Example 74.N-[trans-4-({[3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl]sulfonyl}amino)cyclohexyl]acetamide

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 59, Step 2 substitutingN-(trans-4-aminocyclohexyl)-3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylbenzenesulfonamidebis-hydrochloride (Example 73) forN-(trans-4-aminocyclohexyl)-3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylbenzenesulfonamidehydrochloride (Example 59). ¹H NMR (d₆-DMSO) δ: 8.06 (s, 1H), 7.91 (d,J=2.0 Hz, 1H), 7.78 (s, 1H), 7.78-7.77 (m, 1H), 7.76 (d, J=2.0 Hz, 1H),7.63 (d, J=7.7 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 3.38-3.33 (m, 2H),2.98-2.88 (m, 2H), 2.32 (s, 3H), 1.72 (s, 3H), 1.67 (d, J=10.0 Hz, 2H),1.25-1.14 (m, 2H), 1.12-1.01 (m, 2H). LCMS for C₂₀H₂₆N₇O₃S (M+H)⁺:calculated m/z=444.2; found 444.1.

Example 249.(S)-3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1-hydroxypropan-2-yl)-4-methylbenzenesulfonamide

Step 1. (S)-3-Bromo-N-(1-hydroxypropan-2-yl)-4-methylbenzenesulfonamide

To a mixture of (S)-2-aminopropan-1-ol (55.7 mg, 0.742 mmol, Aldrich)and triethylamine (0.16 mL, 1.1 mmol) in DCM (4.0 mL) at 0° C. was addeddropwise a solution of 3-bromo-4-methylbenzenesulfonyl chloride (100.0mg, 0.371 mmol, Enamine) in DCM (2.0 mL). The reaction mixture wasstirred for one hr at 0° C. Solvent was removed in vacuo and the productwas purified by flash chromatography, eluting with a gradient from 0-17%EtOAc in hexanes to afford a colorless oil (0.096 g, 84%). LCMS forC₁₀H₁₅BrNO₃S (M+H)⁺: calculated m/z=308.0; found 307.9.

Step 2.(S)—N-(1-hydroxypropan-2-yl)-4-methyl-3-(4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

A degassed mixture of(S)-3-bromo-N-(1-hydroxypropan-2-yl)-4-methylbenzenesulfonamide (96 mg,0.31 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(103 mg, 0.405 mmol), potassium acetate (101 mg, 1.03 mmol) anddichlorobis(triphenylphosphine)-palladium(II) (8.8 mg, 0.012 mmol) inTHF (1.5 mL) was heated in a microwave at 140° C. for 20 minutes. Thereaction mixture was cooled to room temperature, diluted with EtOAc andfiltered through Celite™, rinsing with EtOAc. The filtrate was washedwith water and then brine, dried over Na₂SO₄, filtered, andconcentrated. Purification via flash chromatography, eluting with agradient of 0-50% EtOAc in hexanes afforded product as a clear oil(0.136 g, theoretical yield assumed). LCMS for C₁₆H₂₇BNO₅S (M+H)⁺:calculated m/z=356.2; found 356.2.

Step 3. 2-(Trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-4-ol

Ethyl 1-amino-1H-imidazole-2-carboxylate (3.22 g, 20.8 mmol, prepared asin US2015/0274767) and trifluoroacetamidine (9.36 mL, 125 mmol, Oakwood)in EtOH (86 mL) were stirred in an oil bath held at 95° C. for 96 hours.The reaction mixture was allowed to cool to room temperature and thewhite solid product was isolated by filtration (1.42 g, 34%). LCMS forC₆H₄F₃N₄O (M+H)⁺: calculated m/z=205.0; found 205.1. ¹H NMR (400 MHz,CD₃OD) δ 7.77 (s, 1H), 7.49 (s, 1H).

Step 4. 7-Bromo-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-4-ol

A solution of 2-(trifluoromethyl)imidazo[2, l-J][1,2,4]triazin-4-ol(1.46 g, 7.19 mmol) in DMF (25 mL) was treated with NBS (1.41 g, 7.91mmol) for 1 h. The reaction mixture was diluted with water (100 mL),acidified to pH 2 using 1 N HCl, and was extracted with EtOAc twice. Thecombined organic extracts were washed with water (3×100 mL) and brine(100 mL), dried over Na₂SO₄, filtered and concentrated to afford a whitesolid (1.92 g, 95%). LCMS for C₆H₃BrF₃N₄O (M+H)⁺: calculated m/z=282.9,284.9; found 283.0, 285.0. ¹H NMR (400 MHz, CD₃OD) δ 7.67 (s, 1H).

Step 5.7-Bromo-4-chloro-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazine

7-Bromo-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-ol (1.92 g,6.80 mmol) was heated to 110° C. in POCl₃ (20.0 mL, 215 mmol) for 30minutes. Upon cooling to room temperature, POCl₃ was removed in vacuo.The residue was poured into a mixture of ice water. The aqueous mixturewas made basic by the addition of sat'd NaHCO₃ solution, and the mixturewas extracted with EtOAc (3×). The combined organic extracts were driedover sodium sulfate, filtered and concentrated. The product was usedwithout further purification in the next step (2.0 g, 98%). LCMS forC₆H₂BrClF₃N₄(M+H)⁺: calculated m/z=300.9, 302.9; found 301.0, 303.0.

Step 6. 7-Bromo-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-4-amine

A suspension of7-bromo-4-chloro-2-(trifluoromethyl)imidazo[2,1-][1,2,4]triazine (2.0 g,6.6 mmol) in ammonium hydroxide (23 mL, 330 mmol, 14.8 M NH₄OH) washeated to 80° C. in oil bath for 45 minutes. Upon cooling to roomtemperature, water was added and the mixture was extracted with EtOAc(3×). The combined organic extracts were dried over Na₂SO₄, filtered andconcentrated to afford an off-white solid (1.7 g, 92%). LCMS forC₆H₄BrF₃N₅(M+H)⁺: calculated m/z=282.0, 284.0; found 282.0, 284.0. ¹HNMR (400 MHz, CDCl₃) δ 7.72 (s, 1H), 6.75 (br s, 1H), 6.46 (br s, 1H).

Step 7.(S)-3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1-hydroxypropan-2-yl)-4-methylbenzenesulfonamide

A microwave vial was charged with(S)—N-(1-hydroxypropan-2-yl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide(80.0 mg, 0.18 mmol, from Step 2),7-bromo-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine (51 mg,0.18 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (29.0 mg, 0.036 mmol) and THF (14.0 mL) was addedfollowed by the addition of 1 M potassium carbonate solution (0.72 mL,0.72 mmol). The reaction mixture was degassed with N₂ and then heated ina microwave at 140° C. for 30 minutes. The reaction mixture was dilutedwith MeOH and filtered through a plug of Na₂SO₄ and Celite™. Thefiltrate was concentrated. The product was purified by preparativeHPLC-MS (pH 2) to afford 49 mg white solid which suffered some formationof trifluoroacetate ester. The product was then treated with aq. NH₄OHin MeCN, and was re-purified by preparative HPLC-MS (pH 10) to affordproduct as the free base (24 mg, 31%). LCMS for C₁₆H₁₈F₃N₆O₃S (M+H)⁺:calculated m/z=431.1; found 431.2. 1H NMR (500 MHz, DMSO-d₆) δ 8.51 (brs, 2H), 7.96-7.87 (m, 2H), 7.83 (dd, J=8.1, 2.0 Hz, 1H), 7.62 (d, J=8.2Hz, 1H), 4.67 (br s, 1H), 3.36-3.28 (m, 1H), 3.20-3.10 (m, 2H), 2.33 (s,3H), 0.92 (d, 3H).

Example 250.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-4-methylbenzenesulfonamide

Step 1. 3-((tert-Butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylicacid

A mixture of 3-aminobicyclo[1.1.1]pentane-1-carboxylic acid, HCl (500.0mg, 3.06 mmol, PharmaBlock) and N,N-diisopropylethylamine (1.0 mL, 6.1mmol) in THF (10 mL) and water (10 mL) was treated with di-tert-butyldicarbonate (667 mg, 3.06 mmol). After stirring overnight, the reactionwas treated with 1 N HCl to achieve pH 2 and was extracted with EtOAc.

The combined organic extracts were washed with water, brine, dried overNa₂SO₄, filtered and concentrated to afford a white solid (665 mg, 96%).LCMS for C₁₁H₁₇NO₄Na (M+Na)⁺: calculated m/z=250.1; found 250.1.

Step 2. tert-Butyl 3-carbamoylbicyclo[1.1.1]pentan-1-ylcarbamate

A solution of3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid(660 mg, 2.90 mmol) in THF (15 mL) was treated with triethylamine (0.49mL, 3.5 mmol). The resulting mixture was cooled to −15° C. and ethylchloroformate (0.31 mL, 3.2 mmol) was added and the mixture was stirredfor 1 h. To the mixture was added ammonium hydroxide (19.5 mL, 145 mmol)solution. After stirring for 3 hours, THF was evaporated and to thewhite crude solid was added water. The aqueous suspension was extractedwith EtOAc (3×). The combined organic extracts (fine suspension) weredried over Na₂SO₄, and decanted (rather than filtered). The liquiddecanted was concentrated to afford a white solid (0.65 g, 100%). LCMSfor C₁₁H₁₈N₂O₃Na (M+Na)⁺: calculated m/z=249.1, found 249.2. ¹H NMR (400MHz, DMSO-d₆) δ 7.50 (br s, 1H), 7.21 (s, 1H), 6.91 (s, 1H), 2.02 (s,6H), 1.38 (s, 9H).

Step 3. tert-Butyl 3-cyanobicyclo[1.1.1]pentan-1-ylcarbamate

tert-Butyl (3-carbamoylbicyclo[1.1.1]pentan-1-yl)carbamate (200.0 mg,0.884 mmol) in DCM and triethylamine (0.370 mL, 2.65 mmol) at 0° C. wastreated with trichloroacetyl chloride (0.15 mL, 1.3 mmol). After 30minutes, additional triethylamine (0.37 mL, 3.0 eq) and trichloroacetylchloride (0.15 mL, 1.5 eq) were added. After 30 minutes, the reactionwas quenched by the addition of sat'd. NaHCO₃ solution and the aqueousmixture was extracted with EtOAc. The combined organic extracts weredried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash chromatography, eluting with a gradient from 0-100% EtOAc inhexanes and ELSD was used to detect the product which was isolated as awhite solid (107 mg, 58%). ¹H NMR (400 MHz, CDCl₃) δ 5.08 (s, 1H), 2.49(s, 6H), 1.46 (s, 9H).

Step 4. 3-Aminobicyclo[1.1.1]pentane-1-carbonitrile, hydrochloric acidsalt

tert-Butyl (3-cyanobicyclo[1.1.1]pentan-1-yl)carbamate (0.050 g, 0.24mmol) was stirred for 2 hours in 4 M HCl in dioxane (3.0 mL, 12.0 mmol).Volatiles were removed in vacuo to afford product (32 mg, 92%). ¹H NMR(400 MHz, CD₃OD) δ 2.61 (s, 6H).

Step 5.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-4-methylbenzenesulfonamide

To 3-aminobicyclo[1.1.1]pentane-1-carbonitrile, HCl salt (0.160 g, 1.11mmol, prepared as in Step 4) and triethylamine (0.46 mL, 3.3 mmol) inDMA (15 mL) at 0° C. was added 3-(4-aminoimidazo[2,l-J][1,2,4]triazin-7-yl)-4-methylbenzenesulfonyl chloride (0.358 g, 1.11mmol, Prepared as in Example 424, Step 7). The reaction was stirred for2 hours at 0° C. The reaction mixture was poured into pH 7 buffer andEtOAc. The layers were separated and the aqueous layer was extractedwith two further portions of EtOAc. The combined organic extracts werewashed with water (3×), followed by brine, dried over sodium sulfate,filtered and concentrated. The product was purified by preparativeHPLC-MS (pH 2) then repurified at (pH 10) (163 mg, 37%). LCMS forC₁₈H18N₇O₂S (M+H)⁺: calculated m/z=396.1; found 396.1. ¹H NMR (600 MHz,DMSO-d₆) δ 8.36 (s, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.93 (d, J=2.0 Hz,1H), 7.83 (s, 1H), 7.79 (dd, J=8.1, 2.0 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H),2.36 (s, 3H), 2.27 (s, 6H).

Example 251.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

Step 1. 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylicacid

A solution of4-((tert-butoxycarbonyl)amino)bicyclo[2.1.1]hexane-1-carboxylic acid(250 mg, 1.04 mmol) (Spirochem catalog # SPC-a643) and triethylamine(0.17 mL, 1.2 mmol) in THF (5 mL) at −15° C. was treated with ethylchloroformate (0.109 mL, 1.14 mmol) and the reaction was stirred for 1hour. To the mixture was added ammonium hydroxide (14.8 M, 7.0 mL, 52mmol) in one portion. The reaction mixture was stirred at roomtemperature overnight. THF was evaporated, and to the white crude solidwas added water. The aqueous suspension was extracted with EtOAc (3×).The combined organic extracts were dried over Na₂SO₄, filtered andconcentrated to afford product as a white solid (219 mg, 88%). LCMS forC₁₂H₂₁N₂O₃ (M+H)⁺: calculated m/z=241.2, found 241.3. ¹H NMR (400 MHz,DMSO-d₆) δ 7.30 (br s, 1H), 7.07 (s, 1H), 6.83 (s, 1H), 1.93 (br, 2H),1.70 (s, 4H), 1.49 (s, 2H), 1.38 (s, 9H).

Step 2. tert-Butyl (4-cyanobicyclo[2.1.1]hexan-1-yl)carbamate

tert-Butyl (4-carbamoylbicyclo[2.1.1]hexan-1-yl)carbamate (290 mg, 1.21mmol) in DCM (20 mL) containing triethylamine (1.35 mL, 9.65 mmol) at 0°C. was treated with trichloroacetyl chloride (0.54 mL, 4.8 mmol). After40 minutes, the reaction was quenched with saturated NaHCO₃ at 0° C. andthe aqueous mixture was extracted with DCM. The organic extract wasdried over MgSO₄, filtered and concentrated, and the residue waspurified by flash chromatography (eluting with a gradient from 0-20%EtOAc/hexanes) to afford product as a white solid (230 mg, 86%). LCMSfor C₁₂H₁₉N₂O₂ (M+H)⁺: calculated m/z=223.1, found 223.1.

¹H NMR (400 MHz, CD₃OD) δ 2.35 (br, 2H), 2.06-1.98 (m, 2H), 1.90-1.82(m, 2H), 1.82-1.78 (m, 2H), 1.45 (s, 9H).

Step 3. 4-Aminobicyclo[2.1.1]hexane-1-carbonitrile, hydrochloric acidsalt

tert-Butyl (4-cyanobicyclo[2.1.1]hexan-1-yl)carbamate (0.99 g, 4.45mmol, prepared as in Step 2) was dissolved in DCM (50 mL) and 4 N HCl indioxane (11.1 mL, 44 mmol) was added. The mixture was stirred overnightand volatiles were removed in vacuo to afford product as a white solid(0.7 g, 100%). LCMS for C₇H₁₁N₂ (M+H)⁺: calculated m/z=123.1, found123.2.

¹H NMR (500 MHz, DMSO-d₆) δ 9.03 (s, 3H), 2.26-2.20 (m, 2H), 2.11-2.06(m, 2H), 1.89-1.82 (m, 4H).

Step 4.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-methylbenzenesulfonamide,trifluoroacetate salt

1 M Sodium carbonate (0.43 mL, 0.43 mmol) was added to a mixture of4-aminobicyclo[2.1.1]hexane-1-carbonitrile, HCl salt (20.6 mg, 0.130mmol) in DCM (0.6 mL) and acetonitrile (0.3 mL). The mixture was stirredfor 5 minutes, then3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonylchloride (35 mg, 0.11 mmol, prepared as in Example 424, Step 7) wasadded and the reaction was stirred overnight. Purification viapreparative HPLC-MS (pH 2) afforded product as the 1.4×TFA salt (44 mg,71%). LCMS for C₁₉H₂₀N₇O₂S (M+H)⁺: calculated m/z=410.1, found 410.1. 1HNMR (600 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 8.10(s, 1H), 7.96 (d, J=2.1 Hz, 1H), 7.85 (s, 1H), 7.81 (dd, J=8.1, 2.1 Hz,1H), 7.62 (d, J=8.2 Hz, 1H), 2.36 (s, 3H), 2.01-1.93 (m, 2H), 1.92-1.85(m, 2H), 1.74-1.66 (m, 2H), 1.63-1.55 (m, 2H).

Example 252.3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(4-hydroxybicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamide

Step 1. 4-Aminobicyclo[2.1.1]hexane-1-carboxylic acid

To 4-((tert-Butoxycarbonyl)amino)bicyclo[2.1.1]hexane-1-carboxylic acid(200.0 mg, 0.829 mmol, Spirochem) was added 4 N HCl in dioxane (1.0 mL,4.0 mmol) and the reaction was stirred for 3 hours. Volatiles wereremoved in vacuo and the product was used crude in the next step (117mg, 100%).

Step 2. 4-Hydroxybicyclo[2.1.1]hexane-1-carboxylic acid

Sodium nitrite (182 mg, 2.63 mmol) in water (0.2 mL) was added dropwiseto a 10° C. mixture of 4-aminobicyclo[2.1.1]hexane-1-carboxylic acid(117 mg, 0.829 mmol) and 10% acetic acid in water (1.2 mL). The mixturewas then heated to 65° C. and stirred at this temperature overnight. Thereaction mixture was then cooled to 5° C. and potassium hydroxide (370mg, 6.6 mmol) in MeOH (0.8 mL) was added dropwise. The reaction wasagain heated to 65° C. for 3 hours. The reaction mixture was cooled toroom temperature and water was added. The aqueous mixture was washedwith EtOAc (2×). The aqueous layer was cooled to 0° C. and acidified bythe addition of 1 N HCl to pH 3. This acidic aqueous mixture wasextracted with EtOAc (4×). The organic extracts of the acidic aqueouslayer were dried over MgSO₄, filtered and concentrated to afford productwhich was used without further purification (80.0 mg, 68%).

Step 3. Benzyl (4-hydroxybicyclo[2.1.1]hexan-1-yl)carbamate

4-Hydroxybicyclo[2.1.1]hexane-1-carboxylic acid (70.0 mg, 0.49 mmol) intoluene (1 mL) was cooled to 10° C. and was treated with benzyl alcohol(230 μL, 2.2 mmol). The reaction mixture was then treated with DIEA (150μL, 0.86 mmol) and diphenylphosphoryl azide (115 μL, 0.54 mmol). Thereaction mixture was then slowly heated to 110° C. overnight. Thereaction mixture was concentrated to remove solvent and was partitionedbetween EtOAc and brine. The organic layer was dried over MgSO₄,filtered and concentrated. The residue was slurried in DCM and filteredto remove reagent byproducts and the filtrate was purified by flashchromatography, eluting with a gradient of 0-100% EtOAc in hexanes (50.0mg, 41%). ¹H NMR (400 MHz, CD₃OD) δ 7.47-7.15 (m, 5H), 5.14-5.01 (m,2H), 1.88-1.77 (m, 4H), 1.76-1.72 (m, 2H), 1.72-1.63 (m, 2H).

Step 4. 4-Aminobicyclo[2.1.1]hexan-1-ol, hydrochloric acid salt

To a solution of benzyl (4-hydroxybicyclo[2.1.1]hexan-1-yl)carbamate (25mg, 0.10 mmol) in MeOH (2 mL) and water (1 mL) was added palladium (10mg of 10% on carbon) and the reaction mixture was shaken under H₂ at 30psi for 3 hours. The reaction mixture was filtered and MeOH was removedin vacuo. The resulting aqueous mixture was adjusted to pH 3 by theaddition of 1 N HCl and was washed with EtOAc to remove impurities. Theaqueous mixture was then lyophilized to afford product as the HCl salt(7.0 mg, 47%).

Step 5.3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(4-hydroxybicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamide

4-Aminobicyclo[2.1.1]hexan-1-ol HCl salt (7 mg, 0.047 mmol) and DIPEA(8.17 μL, 0.047 mmol) were combined in DCM (0.6 mL) and cooled to 0° C.After stirring for 5 minutes,3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-(methyl-d₃)benzenesulfonylchloride (14.7 mg, 0.037 mmol, prepared as in Example 253, Steps 1through 3, using3-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine in Step 1) in0.5 mL DMA was added. The reaction was allowed to warm to roomtemperature and the mixture was purified by preparative HPLC-MS (pH 10)to afford product as the free base (5.0 mg, 23%). LCMS forC₂₀H₁₈D₃F₃N₅O₃S (M+H)⁺: calculated m/z=471.1, found 471.2. ¹H NMR (400MHz, DMSO-d₆) δ 8.30 (br s, 1H), 7.86 (dd, J=8.1, 2.0 Hz, 1H), 7.83-7.80(m, 2H), 7.71 (br s, 2H), 7.67 (d, J=8.1 Hz, 1H), 7.58 (s, 1H), 5.59 (brs, 1H), 1.65-1.57 (m, 2H), 1.48-1.40 (m, 4H), 1.37-1.31 (m, 2H).

Example 253.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamide(Crystalline Free Base)

Step 1. 4,4,5,5-Tetramethyl-2-(2-(methyl-d₃)phenyl)-1,3,2-dioxaborolane

A degassed mixture of 1-bromo-2-(methyl-d₃)benzene (0.57 g, 3.3 mmol,Combiphos catalog #032D),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.25 g,4.91 mmol, Aldrich), potassium acetate (1.06 g, 10.8 mmol) and1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (0.214 g, 0.262 mmol, Aldrich) in dioxane (16.4mL) was heated to 110° C. for 3 hours. The reaction mixture was cooledto room temperature, diluted with DCM and filtered through Celite®, andthe filtrate was concentrated. Purification via flash chromatography,eluting with a gradient of 0-10% EtOAc in hexanes afforded product (647mg, 89%). LCMS for C₁₃H₁₇D₃BO₂ (M+H)⁺: calculated m/z=222.2, found222.2.

Step 2. 7-(2-(methyl-d₃)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

A microwave vial was charged with4,4,5,5-tetramethyl-2-(2-(methyl-d₃)phenyl)-1,3,2-dioxaborolane (0.34 g,1.5 mmol), 7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine (0.395 g, 1.85mmol, Synthonix),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.251 g, 0.308 mmol, Aldrich) and THF (10 mL)was added followed by the addition of 1 M aq. K₂CO₃ (4.6 mL, 4.6 mmol).The reaction mixture was degassed with N₂ and heated in an oil bath at90° C. for 4 hours, then continued overnight at 80° C. Upon cooling toroom temperature, the mixture was filtered and the solid white product(160 mg) was washed with DCM. Further product was isolated by removingsolvent from the filtrate and isolation of the solid by filtration,washing with water and DCM (total: 217 mg, 62%). LCMS forC₁₂H9D₃N₅(M+H)⁺: calculated m/z=229.1, found 229.1. ¹H NMR (400 MHz,DMSO-d₆) δ 8.20 (s, 2H), 8.04 (s, 1H), 7.68 (s, 1H), 7.52-7.23 (m, 4H).

Step 3.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-(methyl-d₃)benzenesulfonylchloride

7-(2-(methyl-d₃)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine (214 mg,0.937 mmol) in DCM (2 mL) was stirred at 0° C. for 10 minutes.Chlorosulfonic acid (0.44 mL, 6.6 mmol) was added dropwise. The ice bathwas removed, and the reaction mixture was allowed to warm to roomtemperature. After 2.5 hours at room temperature, the mixture was heatedfor 2 hours in an 50° C. oil bath. Upon cooling, the reaction mixturewas diluted with DCM (5 mL) and added to a stirring mixture of ice (10g) and DCM (10 mL) kept in an ice-bath. The precipitated product wasisolated by filtration and rinsed with DCM. The biphasic filtrate wasextracted with DCM (2×), and the combined organic extracts were driedover Na₂SO₄, filtered, and concentrated and the solid so obtained wascombined with the initial solid product isolated by filtration (total:253 mg light yellow solid powder, 83%). LCMS for C₁₂H₅D₃ClN₅O₂S (M+H)⁺:calculated m/z=327.0, found 327.1.

Step 4.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamide

To 4-aminobicyclo[2.1.1]hexane-1-carbonitrile, HCl (2.60 g, 16.4 mmol,prepared as in Example 251, Step 3) in a mixture of DCM (82 mL) andacetonitrile (82 mL) was added 1 M aq. Na₂CO₃ (65 mL, 65 mmol). Afterstirring for 5 minutes,3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-(methyl-d₃)benzenesulfonylchloride (5.62 g, 17.2 mmol, prepared as in Step 3) was added. Thesuspension was stirred overnight. EtOAc (300 mL) and brine (150 mL) wereadded. The layers were separated and the aqueous layer was extractedwith EtOAc (4×300 mL). The combined EtOAc extracts were dried overNa₂SO₄, filtered and concentrated to give crude product as an off-whitesolid (5.8 g). The product was purified by flash chromatography inbatches, eluting with a slow gradient of 0-5% MeOH in DCM to give awhite solid (5.1 g). The purified product was then slurried in acetone(51 mL) overnight. The product as the crystalline free base was isolatedby filtration and air dried to afford the desired product as a whitepowder (4.5 g, 66%). Crystalline free base was characterized by XRPD.The X-Ray Powder Diffraction (XRPD) was obtained from Bruker D2 PHASERX-ray Powder Diffractometer (XRPD) instrument. The general experimentalprocedures for XRPD were: (1) X-ray radiation from copper at 1.054056 Åwith K_(β) filter and LYNXEYE™ detector; (2) X-ray power at 30 kV, 10mA; and (3) the sample powder was dispersed on a zero-background sampleholder. The general measurement conditions for XRPD were: Start Angle 5degrees; Stop Angle 30 degrees; Sampling 0.015 degrees; and Scan speed 2degree/min. The XRPD pattern is shown in FIG. 1 and the XRPD data areprovided in Table 6. LCMS for C₁₉H₁₇D₃N₇O₂S (M+H)⁺: calculatedm/z=413.2, found 413.2. ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.34(s, 1H), 8.25 (s, 1H), 8.08 (s, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.83 (s,1H), 7.81 (dd, J=8.1, 2.1 Hz, 1H), 7.62 (d, J=8.1 Hz, 1H), 2.03-1.93 (m,2H), 1.93-1.81 (m, 2H), 1.78-1.67 (m, 2H), 1.67-1.55 (m, 2H).Crystalline free base was characterized by DSC. The DSC was obtainedfrom TA Instruments Differential Scanning Calorimetry, Model Q2000 withautosampler. The DSC instrument conditions were as follows: 10-300° C.at 10° C./min; Tzero aluminum sample pan and lid; and nitrogen gas flowat 50 mL/min. The DSC thermogram is shown in FIG. 2. The DSC thermogramrevealed one endothermal event at an onset temperature of 232.6° C. witha peak temperature of 234.0° C. which is believed to be themelting/decomposition of the compound. Crystalline free base wascharacterized by TGA. The TGA was obtained from PerkinElmerThermogravimetric Analyzer, Model Pyris 1. The general experimentalconditions for TGA were: ramp from 20° C. to 300° C. at 10° C./min;nitrogen purge gas flow at 60 mL/min; ceramic crucible sample holder.The TGA thermogram is shown in FIG. 3. A weight loss of about 0.4%between 150° C. and 250° C. which is believed to be the decomposition.The compound further decomposes above 250° C.

TABLE 6 2-Theta (°) Net Intensity Relative Intensity (%) 7.9 1446 6.48.4 2441 10.9 9.3 770 3.4 10.5 1655 7.4 12.0 2110 9.4 12.3 1167 5.2 12.5828 3.7 12.7 275 1.2 13.0 143 0.6 13.5 1778 7.9 14.4 329 1.5 15.3 246411.0 15.7 283 1.3 16.5 858 3.8 16.9 22415 100 17.3 2564 11.4 17.6 654229.2 17.4 2272 10.1 18.6 873 3.9 18.8 340 1.5 19.4 2394 10.7 19.9 19608.7 20.6 3902 17.4 21.0 616 2.7 21.1 561 2.5 21.3 324 1.4 21.9 700 3.122.2 548 2.4 22.6 169 0.8 23.2 1528 6.8 23.6 278 1.2 23.9 1350 6.0 24.11139 5.1 24.4 1049 4.7 24.9 8538 38.1 25.5 1651 7.4 26.1 291 1.3 26.2469 2.1 26.5 3588 16.0 27.1 1837 8.2 27.6 169 0.8 28.1 168 0.7 28.6 9004.0 29.3 180 0.8

Example 254.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamidecrystalline hydrochloric acid salt

Hydrochloric acid (1.07 mL, 2.67 mmol) (2.5 M solution in EtOH) wasadded to a suspension of3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamide(1.0 g, 2.4 mmol, from Example 253) in acetone (40.0 mL). The solventwas removed from the solution in vacuo to afford a solid. Ethyl acetate(9.9 mL, 100 mmol) was added and the mixture was stirred at roomtemperature for 2.5 hours. The solid was isolated by filtration anddried on funnel under house vacuum for 2 hours, followed by overnightunder vacuum/N₂ stream. (1.02 g, 94%). The hydrochloric acid salt wasshown to be a 1:1 salt by chloride titration and was characterized byXRPD. Experimental parameters for acquiring the XRPD data are asdescribed in Example 253. The XRPD pattern is shown in FIG. 4 and theXRPD data are provided in Table 7. LCMS for C₁₉H₁₇D₃N₇O₂S (M+H)⁺:calculated m/z=413.2, found 413.0. ¹H NMR (500 MHz, DMSO-d₆) δ 8.91 (s,1H), 8.75 (s, 1H), 8.74 (s, 1H), 8.20 (s, 1H), 7.99 (s, 1H), 7.96 (d,J=2.0 Hz, 1H), 7.84 (dd, J=8.1, 2.1 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H),2.02-1.93 (m, 2H), 1.92-1.84 (m, 2H), 1.74-1.66 (m, 2H), 1.63-1.56 (m,2H). Crystalline hydrochloric acid salt was characterized by DSC.Experimental parameters for acquiring the DSC data are as described inExample 253. The DSC thermogram is shown in FIG. 5. The DSC thermogramrevealed one major endothermal event at an onset temperature of 211.3°C. with a peak temperature of 233.4° C. which is believed to be themelting/decomposition of the compound. Crystalline hydrochloric acidsalt was characterized by TGA. Experimental parameters for acquiring theTGA data are as described in Example 253. The TGA thermogram is shown inFIG. 6. A weight loss of about 6.8% below 220° C. in the first step anda weight loss of about 2.7% between 220° C. and 300° C. in the secondstep were observed and believed to be associated with the decompositionof the compound.

TABLE 7 2-Theta (°) Net Intensity Relative Intensity (%) 7.1 228 3.8 9.7563 9.4 9.9 1507 25.2 11.3 57 0.9 12.5 205 3.4 13.4 4704 78.6 14.1 162527.1 15.1 445 7.4 15.6 348 5.8 15.8 1475 24.6 16.1 3276 54.7 16.2 187431.3 16.5 1138 19.0 17.4 5988 100 18.0 4434 74.0 19.3 746 12.5 19.9 3786.3 20.9 384 6.4 21.3 711 11.9 21.7 1938 32.4 22.0 3390 56.6 22.4 110718.5 23.4 776 13.0 23.9 83 1.4 24.5 1039 17.4 25.3 804 13.4 26.4 80513.4 26.8 1201 20.1 27.9 1298 21.7 29.2 598 10.0

Example 255.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamidecrystalline benzenesulfonic acid salt

To3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamide(1.00 g, 2.424 mmol, from Example 253) in acetone (40.0 mL) was addedbenzenesulfonic acid in THF (1 M, 2.67 mL, 2.67 mmol) to obtain asolution. The acetone was removed in vacuo and the solid was slurried inethyl acetate (10 mL) and was stirred for 1.5 hours. The solid wasisolated by filtration, washed with a small amount of EtOAc and hexanes.The solid product was air dried for 2 hours and under vacuum/N₂ streamovernight at 50° C. (1.3 g, 94%). The benzenesulfonic acid salt wasshown to be a 1:1 salt by ¹H NMR and was characterized by XRPD.Experimental parameters for acquiring the XRPD data are as described inExample 253. The XRPD pattern is shown in FIG. 7 and the XRPD data areprovided in Table 8. LCMS for C₁₉H₁₇D₃N₇O₂S (M+H)⁺: calculatedm/z=413.2, found 413.1. ¹H NMR (400 MHz, CD₃OD) δ 8.30 (s, 1H), 8.04 (d,J=2.0 Hz, 1H), 8.01 (s, 1H), 7.93 (dd, J=8.2, 2.1 Hz, 1H), 7.88-7.82 (m,2H), 7.65 (d, J=8.2 Hz, 1H), 7.48-7.40 (m, 3H), 2.15-2.05 (m, 2H),1.99-1.91 (m, 2H), 1.86-1.79 (m, 2H), 1.69-1.60 (m, 2H). Crystallinebesylate salt was characterized by DSC. Experimental parameters foracquiring the DSC data are as described in Example 253. The DSCthermogram is shown in FIG. 8. The DSC thermogram revealed oneendothermal event at an onset temperature of 211.0° C. with a peaktemperature of 213.8° C. which is believed to be themelting/decomposition of the compound. Crystalline besylate salt wascharacterized by TGA. Experimental parameters for acquiring the TGA dataare as described in Example 253. The TGA thermogram is shown in FIG. 9.A weight loss of about 0.4% between 150° C. and 230° C. was observed inthe first step and followed by a significant weight loss above 230° C.which is believed to be associated with the decomposition of thecompound.

TABLE 8 2-Theta (°) Net Intensity Relative Intensity (%) 6.5 1795 26.78.0 374 5.6 8.9 83 1.2 9.9 5204 77.5 10.5 5702 84.9 11.2 809 12.0 12.2477 7.1 13.1 621 9.3 14.3 808 12.0 14.8 3627 54.0 15.8 3818 56.9 16.54198 62.5 16.7 6714 100 17.1 4294 64.0 17.3 1001 14.9 17.9 591 8.8 18.62402 35.8 18.9 4034 60.1 19.2 2278 33.9 19.8 2131 31.7 20.3 1593 23.721.0 694 10.3 21.2 1626 24.2 21.8 918 13.7 22.2 2303 34.3 22.8 3238 48.223.6 2104 31.3 23.9 729 10.9 24.5 2109 31.4 24.9 2275 33.9 26.0 726 10.825.9 1789 26.6 26.3 986 14.7 26.8 353 5.3 27.1 197 2.9 27.7 562 8.4 28.51018 15.2 28.7 572 8.5 29.2 482 7.2 29.7 569 8.5

Example 256.5-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-methylpyridine-3-sulfonamidetrifluoroacetate salt

Step 1. 5-Bromo-6-methylpyridine-3-sulfonyl chloride

A round-bottom flask was charged with water (7.5 mL, 41 mmol) and cooledin an ice bath. To this was added thionyl chloride (1.23 mL, 16.9 mmol)over 15 minutes. The reaction mixture was then warmed to roomtemperature using a warm water bath, and copper(I) chloride (0.018 g,0.18 mmol) was added. The reaction mixture was placed in a brine-icebath.

Concurrently in a separate round-bottom flask,5-bromo-6-methylpyridin-3-amine (0.686 g, 3.67 mmol, Combi-Blocks) wasdissolved in 12 N HCl (7.3 mL, 88 mmol). After a few minutes, whitesolids were observed. This mixture was also placed in a brine-ice bath.A solution of sodium nitrite (0.278 g, 4.03 mmol) in water (0.99 mL, 55mmol) was added over 1-2 minutes, giving dissolution of solids. Afterstirring for 5 minutes, this mixture was slowly added (over 5 minutes)to the thionyl chloride solution generated above. After 2 hours, thereaction mixture was warmed to room temperature and stirred for 1 hour.DCM (15 mL) and DI water (25 mL) were added to the reaction mixture.Solid sodium bicarbonate (11.1 g, 132 mmol) was added in portions untilpH 7. Water and ethyl acetate were added and the layers were separated.The aqueous layer was extracted with EtOAc (2×). The combined organicextracts were washed with brine, dried with magnesium sulfate, filtered,and concentrated to give a brown oil, which was used without furtherpurification (440 mg, 44%).

Step 2.5-Bromo-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-methylpyridine-3-sulfonamide

4-Aminobicyclo[2.1.1]hexane-1-carbonitrile, HCl salt (36 mg, 0.23 mmol)in DCM (2 mL) containing DIPEA (0.097 mL, 0.55 mmol) was cooled to 0° C.and stirred for 5 minutes, at which time5-bromo-6-methylpyridine-3-sulfonyl chloride (50.0 mg, 0.185 mmol, fromStep 1) in DCM (0.5 mL) was added. After 1 hour, water was added and thelayers were separated. The aqueous layer was extracted with EtOAc (3×).The combined organic extracts were washed with brine, dried over MgSO₄,filtered and concentrated. The product was purified by flashchromatography, eluting with a gradient from 0-100% EtOAc in hexanes toprovide desired product as a clear oil (50.0 mg, 62%). LCMS forC₁₃H₁₅BrN₃O₂S (M+H)⁺: calculated m/z=356.0, found 356.1. ¹H NMR (400MHz, CD₃OD) δ 8.84 (d, J=2.0 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H), 2.75 (s,3H), 2.19-2.07 (m, 2H), 2.01-1.94 (m, 2H), 1.85-1.74 (m, 2H), 1.74-1.62(m, 2H).

Step 3.N-(4-Cyanobicyclo[2.1.1]hexan-1-yl)-6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide

A microwave vial was charged with bis(pinacolato)diboron (0.036 g, 0.14mmol, Aldrich), potassium acetate (0.045 g, 0.46 mmol) and5-bromo-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-methylpyridine-3-sulfonamide(0.050 g, 0.14 mmol) as a solution in THF (2 mL). The reaction mixturewas sparged with nitrogen for 5 minutes. To this mixture was addedbis(triphenylphosphine)palladium(II) chloride (0.099 g, 0.14 mmol), andthe mixture was sealed and heated to 80° C. overnight. Upon cooling toroom temperature, the reaction mixture was diluted with EtOAc and washedwith water. The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated to afford product, which was used withoutfurther purification (55 mg, 97%). LCMS for C₁₉H₂₇BN₃O₄S (M+H)⁺:calculated m/z=404.2, found 404.1.

Step 4.5-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-methylpyridine-3-sulfonamide,trifluoroacetate salt

To a degassed mixture of 7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine(6.4 mg, 0.030 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (2.4 mg, 3.0 μmol, Aldrich), andN-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide(12 mg, 0.030 mmol) in THF (1.0 mL) was added Na₂CO₃ (7.9 mg, 0.074mmol) in water (0.2 mL), and the reaction was heated to 80° C. for 3hours. The reaction mixture was diluted with MeOH, filtered and purifiedvia preparative HPLC-MS (pH 2) to afford product as the TFA salt (6 mg,40%). LCMS for C₁₈H₁₉N₅O₂S (M+H)⁺: calculated m/z=411.1, found 411.1. ¹HNMR (400 MHz, CD₃OD) δ 8.97 (d, J=2.2 Hz, 1H), 8.47 (d, J=2.3 Hz, 1H),8.16 (s, 1H), 7.91 (s, 1H), 2.67 (s, 3H), 2.22-2.13 (m, 2H), 2.01-1.92(m, 2H), 1.92-1.82 (m, 2H), 1.80-1.67 (m, 2H).

Example 257.5-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-methylpyridine-3-sulfonamide

Prepared as in Example 256 using3-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine (Example 472,Step 6) in Step 4 followed by purification via preparative HPLC-MS (pH10) to afford the title compound (6 mg, 30%). LCMS for C₂₀H₁₉F₃N₇O₂S(M+H)⁺: calculated m/z=478.1, found 478.2. ¹H NMR (400 MHz, CD₃OD) δ9.05 (d, J=2.3 Hz, 1H), 8.27 (d, J=2.3 Hz, 1H), 7.84 (s, 1H), 7.75 (s,1H), 2.54 (s, 3H), 2.21-2.12 (m, 2H), 2.03-1.90 (m, 2H), 1.90-1.79 (m,2H), 1.79-1.69 (m, 2H).

Example 258.3-(4-Amino-6-methylimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamidetrifluoroacetate salt

Step 1. 3-Bromo-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide

1 M Na₂CO₃ solution (0.78 mL, 0.78 mmol) was added to4-aminobicyclo[2.1.1]hexane-1-carbonitrile, HCl salt (37 mg, 0.24 mmol,from 251, Step 3) in DCM (1.0 mL) and acetonitrile (0.5 mL). After 5minutes, 3-bromobenzenesulfonyl chloride (0.028 mL, 0.196 mmol,Combi-Blocks) was added. The reaction was allowed to warm to roomtemperature and was stirred overnight. The layers were separated and theaqueous layer was extracted with two portions of DCM. The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated. Flash chromatography, eluting with a gradient from 0-100%EtOAc in hexanes and using ELSD for detection afforded purified product(64 mg, 96%). LCMS for C₁₃H₁₄BrN₂O₂S (M+H)⁺: calculated m/z=341.0, found341.0.

Step 2.N-(4-Cyanobicyclo[2.1.1]hexan-1-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

A mixture of3-bromo-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide (64.0 mg,0.188 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(61.9 mg, 0.244 mmol), potassium acetate (61 mg, 0.62 mmol) anddichlorobis(triphenylphosphine)-palladium(II) (5.3 mg, 7.5 μmol) in THF(1.9 mL) was degassed and the mixture was heated in a microwave at 140°C. for 30 minutes. Upon cooling to room temperature, the reactionmixture was diluted with water and EtOAc. The layers were separated andthe aqueous portion was extracted with two further portions of EtOAc.The combined organic extracts were washed with brine and dried oversodium sulfate, filtered and concentrated. The product was used withoutfurther purification in Step 3. LCMS for C₁₉H₂₆BN₂O₄S (M+H)⁺: calculatedm/z=389.2, found 389.2.

Step 3.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide

A microwave vial was charged withN-(4-cyanobicyclo[2.1.1]hexan-1-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide(70.0 mg, 0.180 mmol), 7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine (46mg, 0.22 mmol, Synthonix) and THF (1.8 mL), followed by the addition of1 M aq. K₂CO₃ (0.54 mL, 0.54 mmol). The reaction mixture was degassedand heated to 90° C. for 3.5 hours. Upon cooling to room temperature,the reaction mixture was partitioned between water and EtOAc. Theaqueous layer was extracted with two further portions of EtOAc. Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated. The product was purified by flash chromatography, elutingwith a gradient from 0-100% EtOAc in hexanes to afford a white solid (68mg, 95%). LCMS for C₁₈H₁₈N₇O₂S (M+H)⁺: calculated m/z=396.1, found396.1.

Step 4.3-(4-Amino-6-bromoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide

A solution of3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide(68 mg, 0.17 mmol) and N-bromosuccinimide (37 mg, 0.21 mmol) in DMF (1.5mL) was heated to 50° C. for 2 hours. Upon cooling to room temperature,the reaction mixture was diluted with EtOAc, washed with water andbrine, dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography, eluting with a gradient from 0-100%EtOAc/hexanes to afford product (23 mg, 28%). LCMS for C₁₈H₁₇BrN₇O₂S(M+H)⁺: calculated m/z=474.0, found 474.1.

Step 5.3-(4-amino-6-methylimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide,trifluoroacetate salt

To a degassed solution of3-(4-amino-6-bromoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide(0.010 g, 0.021 mmol) in THF (0.5 mL) was addedtetrakis(triphenylphosphine)palladium(0) (2.4 mg, 2.1 μmol), followed by2.0 M trimethylaluminum in hexanes (0.032 mL, 0.063 mmol). The reactionwas sealed and heated to 100° C. for 45 minutes. Additionaltrimethylaluminum (2.0 M in hexanes, 0.032 mL, 0.063 mmol) wasintroduced, and heating was continued for 2 hours. Upon cooling to roomtemperature, a few drops of water were added and MeCN was added to makethe mixture monophasic. The mixture was stirred until gas evolutionsubsided and then was filtered, diluted with methanol, and the mixturewas purified by preparative HPLC-MS (pH 2) to afford product as thetrifluoroacetate salt (7.0 mg, 60%). LCMS for C₁₉H₂₀N₇O₂S (M+H)⁺:calculated m/z=410.1, found 410.2. ¹H NMR (400 MHz, CD₃OD) δ 8.32-8.28(m, 1H), 8.15 (s, 1H), 7.99-7.94 (m, 2H), 7.77 (t, J=7.9 Hz, 1H), 2.59(s, 3H), 2.18-2.10 (m, 2H), 2.01-1.92 (m, 2H), 1.89-1.80 (m, 2H),1.72-1.61 (m, 2H).

Example 259.3-(4-Amino-2-cyclopropylimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

Step 1. 2-Cyclopropylimidazo[2,1-f][1,2,4]triazin-4-ol

Dry HCl gas was bubbled through a solution of ethyl1-amino-1H-imidazole-2-carboxylate (0.240 g, 1.55 mmol, prepared as inUS2015/0274767) and cyclopropanecarbonitrile (0.519 g, 7.73 mmol, AlfaAesar) in dioxane (2.4 mL) for 2 minutes, during which time the solutionbecame a suspension, then returned to a solution. This solution washeated in a sealed reaction vial to 110° C. for 5.5 hours. Upon coolingto room temperature, solvent was evaporated to afford a sticky solid,which was triturated with EtOAc and stirred overnight and the solidproduct was filtered off and air dried. LCMS for C₈H9N₄O (M+H)⁺:calculated m/z=177.1, found 177.1.

Step 2. 7-Bromo-2-cyclopropylimidazo[2,1-f][1,2,4]triazin-4-ol

A solution of 2-cyclopropylimidazo[2,1-f][1,2,4]triazin-4-ol (0.330 g,1.87 mmol, prepared as in Step 1) in DMF (10.0 mL) was treated with NBS(0.367 g, 2.06 mmol) and the mixture was stirred at room temperature for2 hours. The reaction mixture was diluted with water and sodiumthiosulfate solution was added. 1 N HCl was added to achieve pH 3 andthe aqueous mixture was extracted with four portions of EtOAc (4×50 mL).The combined organic extracts were dried over sodium sulfate, filteredand concentrated to afford a solid which was azeotroped with heptane onthe rotovap to afford an off-white solid. LCMS for C₈H₈BrN₄O (M+H)⁺:calculated m/z=255.0, found 255.0.

Step 3. 7-Bromo-4-chloro-2-cyclopropylimidazo[2,1-f][1,2,4]triazine

7-Bromo-2-cyclopropylimidazo[2,1-f][1,2,4]triazin-4-ol (0.378 g, 1.48mmol) was heated in POCl₃ (6.9 mL, 74 mmol) to 110° C. overnight and thereaction was less than half complete. N,N-dimethylaniline (0.19 mL, 1.5mmol) and tetraethylammonium chloride (0.491 g, 2.96 mmol) were added.The reaction mixture was sealed and heating was continued for 2 hours,at which point the reaction was complete. POCl₃ was removed on therotovap and the residue was poured onto crushed ice, then the aqueousmixture was made basic by the addition of solid NaHCO₃. The aqueousmixture was extracted with EtOAc (3×). The combined organic extractswere dried over sodium sulfate, filtered and concentrated. The productwas used without further purification. LCMS for C₈H₇BrClN₄ (M+H)⁺:calculated m/z=273.0, found 273.0.

Step 4. 7-Bromo-2-cyclopropylimidazo[2,1-f][1,2,4]triazin-4-amine

A suspension of7-bromo-4-chloro-2-cyclopropylimidazo[2,1-][1,2,4]triazine (0.512 g,1.87 mmol, prepared as in Step 3) in ammonium hydroxide (14.8 M, 13 mL,190 mmol) was heated to 80° C. for 30 minutes, then at room temperatureovernight. Brine was added and the mixture was extracted with EtOAc (3x). The combined organic extracts were dried over Na₂SO₄, filtered andconcentrated. The product was purified by flash chromatography, elutingwith a gradient from 0-100% EtOAc in hexanes to obtain desired productas white solid (140 mg, 29%). LCMS for C₈H₉BrN₅ (M+H)⁺: calculatedm/z=254.0, found 254.0. ¹H NMR (400 MHz, CDCl₃) δ 7.52 (s, 1H), 2.14(tt, J=8.2, 4.8 Hz, 1H), 1.11 (dt, J=6.1, 3.1 Hz, 2H), 1.01 (dt, J=8.2,3.1 Hz, 2H).

Step 5. (4-Aminobicyclo[2.1.1]hexan-1-yl)methanol trifluoroacetate salt

Ethyl chloroformate (0.131 mL, 1.37 mmol) was added dropwise to asolution of4-((tert-butoxycarbonyl)amino)bicyclo[2.1.1]hexane-1-carboxylic acid(0.300 g, 1.24 mmol, Enamine catalog # EN300-70833) and triethylamine(0.26 mL, 1.9 mmol) in THF (5 mL) at −5° C. The reaction was stirred for30 minutes at this temperature. The solid formed was filtered and washedwith 2 mL THF. The pooled washings and filtrate were cooled to 0° C. andtreated with sodium borohydride (141 mg, 3.73 mmol) in one portionfollowed by MeOH (2 mL), added dropwise. After 30 minutes, the reactionmixture was quenched by the addition of water and 2N HCl. The layerswere separated, and the aqueous layer was extracted several times withEtOAc. The combined organic extracts were dried over MgSO₄, filtered andconcentrated. LCMS for C₈H₄NO₃ (M−^(t)Bu+H)⁺: calculated m/z=172.1,found 172.1.

tert-Butyl (4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)carbamate obtainedabove was dissolved in DCM (1 mL), trifluoroacetic acid (0.96 mL, 12.0mmol) was added and reaction was stirred for 2 hours. Volatiles wereremoved in vacuo to afford product as the trifluoroacetate salt (0.15 g,55%). LCMS for C₇H₄NO (M+H)⁺: calculated m/z=128.1, found 128.1.

Step 6.N-(4-(Hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

Prepared from (4-aminobicyclo[2.1.1]hexan-1-yl)methanol trifluoroacetatesalt analogously to the procedure for Example 249, Steps 1 through 2.LCMS for C₂₀H₃₁BNO₅S (M+H)⁺: calculated m/z=408.2, found 408.1.

Step 7.3-(4-Amino-2-cyclopropylimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-4-methylbenzenesulfonamide,trifluoroacetate salt

1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (1.6 mg, 2.0 μmol) was added to a degassedmixture of 7-bromo-2-cyclopropylimidazo[2,1-f][1,2,4]triazin-4-amine(5.0 mg, 0.020 mmol),N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide(8.0 mg, 0.020 mmol, from Step 6), and sodium carbonate (6.2 mg, 0.059mmol) in dioxane (2 mL) and water (1 mL) and the mixture was heated to120° C. for 3 hours. The reaction was diluted with MeOH and purified viapreparative HPLC-MS (pH 2) to obtain the desired product as a whitesolid (1.0 mg, 9%). LCMS for C₂₂H₂₇N₆O₃S (M+H)⁺: calculated m/z=455.2,found 455.1.

Example 260.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamidetrifluoroacetate salt

Step 1. 7-(2-Chlorophenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

A degassed mixture of 7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine (96mg, 0.45 mmol, Synthonix), (2-chlorophenyl)boronic acid (0.070 g, 0.45mmol, Aldrich) and1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (37 mg, 0.045 mmol) in dioxane (2 mL) and sodiumcarbonate (142 mg, 1.34 mmol) in water (1 mL) was heated to 120° C. for3 hours. Upon cooling, the reaction mixture was diluted with water andEtOAc and the phases were separated. The product was identified aspresent in the aqueous layer as a suspension. The aqueous layer wasfiltered and the off white solid was air dried (0.100 g, 91%). LCMS forC₁₁H₉ClN₅ (M+H)⁺: calculated m/z=246.1, found 246.1.

Step 2.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-chlorobenzenesulfonylchloride

7-(2-Chlorophenyl)imidazo[2,1-f][1,2,4]triazin-4-amine (0.030 g, 0.12mmol) in DCM (10 mL) and under N₂ at 0° C. was treated withchlorosulfonic acid (0.081 mL, 1.22 mmol), added dropwise. The ice bathwas removed. The mixture was warmed to room temperature and stirred for1 hour, followed by heating to 50° C. overnight. The reaction mixturewas diluted with DCM and added to stirred ice water. After the icemelted, layers were separated and the aqueous layer was extracted withDCM (2 x). The combined extracts were dried over MgSO₄, filtered andconcentrated. The product was purified by flash chromatography, elutingwith a gradient from 0-100%, EtOAc in Hexanes, and was isolated as alight yellow oil (0.030 g, 71%). LCMS for C₁₁H₈Cl₂N₅O₂S (M+H)⁺:calculated m/z=344.0, found 344.0.

Step 3.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-chloro-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide

To 4-aminobicyclo[2.1.1]hexane-1-carbonitrile, HCl (8.3 mg, 0.052 mmol,from Example 251, Step 3) in DCM (0.6 mL) and acetonitrile (0.3 mL) wasadded 1 M Na₂CO₃ (0.17 mL, 0.17 mmol). The mixture was stirred for 5minutes, then3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-chlorobenzenesulfonylchloride (15 mg, 0.044 mmol) was added. DMA (1 mL) was added to aidsolubility. The reaction was stirred for 2 hours. Purification via flashchromatography, eluting with a gradient from 0-100% EtOAc in hexanes)afforded product as colorless oil. (0.015 g, 80%). LCMS forC₁₈H₁₇ClN₇O₂S (M+H)⁺: calculated m/z=430.1, found 430.1.

Step 4.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide,trifluoroacetate salt

A degassed mixture of3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-chloro-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide(15 mg, 0.035 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.6 mg,1.7 μmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.4 mg, 3.5μmol), and zinc cyanide (8.2 mg, 0.070 mmol) in a mixture of DMF (2 mL)and water (20 μL) was heated in microwave at 150° C. for 30 minutes. Thecrude reaction mixture was filtered and purified via preparative HPLC-MS(pH 2) to afford product as a white solid (5.0 mg, 27%). LCMS forC₁₉H₁₇N₈O₂S (M+H)⁺: calculated m/z=421.1, found 421.1. ¹H NMR (600 MHz,DMSO-d₆) δ 9.09 (s, 1H), 8.52 (s, 1H), 8.49 (d, J=1.7 Hz, 1H), 8.43 (s,1H), 8.28 (d, J=8.3 Hz, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 8.02 (dd,J=8.2, 1.9 Hz, 1H), 2.07-1.99 (m, 2H), 1.93-1.87 (m, 2H), 1.76-1.70 (m,2H), 1.69-1.63 (m, 2H).

Example 261.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-N-methyl-4-(methyl-d₃)benzenesulfonamide

Step 1. 4-(Methylamino)bicyclo[2.1.1]hexane-1-carbonitrile, hydrochloricacid salt

Sodium hydride (60% in mineral oil, 1.2 mg, 0.049 mmol) was added to amixture of tert-butyl (4-cyanobicyclo[2.1.1]hexan-1-yl)carbamate (0.010g, 0.045 mmol, prepared as in Example 251, Step 2) in DMF (1 mL) at 0°C. After the reaction mixture was stirred for 5 minutes, it was treatedwith methyl iodide (3 μL, 0.05 mmol). After stirring for 2 hours at 0°C., water was added and the mixture was extracted with EtOAc. Theorganic extract was washed with brine, dried over MgSO₄, filtered andconcentrated. The crude product was treated with HCl (4M in dioxane)(0.5 mL, 2 mmol) and was stirred for 1 hour. Volatiles were removed invacuo and the product was used without further purification in Step 2.Theoretical yield was assumed. LCMS for C₈H₁₃N₂(M+H)⁺: calculatedm/z=137.1, found 137.2.

Step 2.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-N-methyl-4-(methyl-d₃)benzenesulfonamide

To 4-(methylamino)bicyclo[2.1.1]hexane-1-carbonitrile, HCl (5 mg, 0.03mmol, from Step 1) in DCM (0.6 mL) was added Hunig's base (5 μL, 0.03mmol) and the mixture was cooled to 0° C. After stirring for 5 minutes,3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-(methyl-d₃)benzenesulfonylchloride (7.6 mg, 0.023 mmol, Example 253, Step 3) in 0.5 mL DMA wasadded. The mixture was allowed to warm to room temperature over 30minutes, and the product was purified by preparative HPLC-MS (pH 10) toafford a white solid (4.0 mg, 30%). LCMS for C₂₀H₁₉D₃N₇O₂S (M+H)⁺:calculated m/z=427.2, found 427.2. ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (s,1H), 8.25 (s, 1H), 8.09 (s, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.85 (s, 1H),7.80 (dd, J=8.1, 2.0 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 2.82 (s, 3H),2.19-2.07 (m, 2H), 2.02-1.85 (m, 4H), 1.71-1.54 (m, 2H).

The following Examples provided in Tables 9-19 were prepared accordingto Method A or Method B, unless otherwise noted.

TABLE 9

LCMS Ex. Name −N(R)₂ [M + H]⁺ No. NMR Spectra 262^(A)3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-4- methylbenzenesulfonamide

428.1 ¹H NMR (400 MHz, CD₃OD) δ 7.95 (dd, J = 8.1, 1.8 Hz, 1H), 7.85 (d,J = 1.7 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.61 (s, 1H), 7.06 (s, 1H),3.54 (s, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 1.82 − 1.71 (m, 2H), 1.59 −1.51 (m, 2H), 1.51 − 1.42 (m, 2H), 1.26 − 1.13 (m, 2H) 263^(A)3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

423.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.77 (s, 1H), 7.94 − 7.91 (m, 2H),7.78 (d, J = 1.6 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.25 (s, 1H), 2.25(s, 6H), 2.02 − 1.93 (m, 2H), 1.93 − 1.84 (m, 2H), 1.74 − 1.66 (m, 2H),1.66 − 1.53 (m, 2H) 264^(B)3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

409.1

TABLE 10

LCMS Ex. Name −N(R)₂ [M + H]⁺ No. NMR Spectra 265^(B)3-(4-Amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

424.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (s, 1H), 8.40 (s, 1H), 8.28 (s,1H), 7.95 (d, J = 1.9 Hz, 1H), 7.81 (dd, J = 8.1, 2.0 Hz, 1H), 7.79 (s,1H), 7.62 (d, J = 8.2 Hz, 1H), 2.36 (s, 3H), 2.30 (s, 3H), 2.02 − 1.93(m, 2H), 1.93 − 1.84 (m, 2H), 1.74 − 1.68 (m, 2H), 1.64 − 1.56 (m, 2H)266^(A) 3-(4-Amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(3,3,3-trifluoro-2-hydroxypropyl) benzenesulfonamide (singleenantiomer isolated)

431.1 ¹H NMR (600 MHz, DMSO-d₆) δ 8.21 (s, 1H), 8.13 (s, 1H), 7.91 (d, J= 2.0 Hz, 1H), 7.79 (dd, J = 8.1, 2.0 Hz, 1H), 7.73 (s, 1H), 7.62 (d, J= 8.2 Hz, 1H), 6.63 (br s, 1H), 4.10 − 3.96 (m, 1H), 3.06 (dd, J = 13.6,4.1 Hz, 1H), 2.90 (dd, J = 13.6, 7.9 Hz, 1H), 2.34 (s, 3H), 2.27 (s,3H). 267^(A) 3-(4-Amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(3,3,3-trifluoro-2- hydroxypropyl)benzenesulfonamide (singleenantiomer isolated)

431.1 ¹H NMR (400MHz, DMSO-d₆) δ 8.27 (s, 1H), 8.18 (s, 1H), 7.98 (t, J= 6.1 Hz, 1H), 7.91 (d, J = 1.3 Hz, 1H), 7.80 (dd, J = 7.8, 1.2 Hz, 1H),7.75 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 6.60 (br s, 1H), 3.12 − 2.99 (m,1H), 2.95 − 2.86 (m, 1H), 2.34 (s, 3H), 2.28 (s, 3H) 268^(A)3-(4-Amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-4- methylbenzenesulfonamidetrifluoroacetate salt

429.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.33 (s, 1H), 8.28 (s, 1H), 8.19 (s,1H), 7.93 (d, J = 1.6 Hz, 1H), 7.79 (dd, J = 8.0, 1.7 Hz, 1H), 7.74 (s,1H), 7.59 (d, J = 8.1 Hz, 1H), 3.35 (s, 2H), 2.34 (s, 3H), 2.28 (d, J =4.8 Hz, 3H), 1.76 − 1.59 (m, 2H), 1.44 − 1.39 (m, 2H), 1.38 − 1.28 (m,2H), 1.12 − 0.97 (m, 2H) 269^(A)3-(4-Amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1-hydroxycyclobutyl)methyl)-4-methylbenzenesulfonamide trifluoroacetatesalt

403.1 ¹H NMR (600 MHz, DMSO-d₆) δ 8.28 (s, 1H), 8.18 (s, 1H), 7.92 (d, J= 2.0 Hz, 1H), 7.81 (dd, J = 8.0, 2.0 Hz, 1H), 7.74 (s, 1H), 7.60 (d, J= 8.1 Hz, 1H), 7.53 (t, J = 6.4 Hz, 1H), 2.83 (d, J = 6.4 Hz, 2H), 2.32(s, 3H), 2.29 (s, 3H), 2.04 − 1.95 (m, 2H), 1.92 − 1.82 (m, 2H), 1.65 −1.55 (m, 1H), 1.45 − 1.35 (m, 1H). 270^(B)3-(4-Amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

410.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (s, 1H), 8.27 (s, 1H), 8.19 (s,1H), 7.94 − 7.89 (m, 1H), 7.81 − 7.71 (m, 2H), 7.64 (d, , J = 8.0 Hz,1H), 2.37 (s, 3H), 2.29 (s, 9H) 271^(A)3-(4-amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-4- methylbenzenesulfonamidetrifluoroacetate salt

431.1 272^(A) 3-(4-amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1r,3r)-3-cyanocyclobutyl)-4-methylbenzenesulfonamide trifluoroacetatesalt

398.1 273^(A)3-(4-amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamide trifluoroacetate salt

391.1 ¹H NMR (600 MHz, DMSO) δ 8.50 (s, 1H), 8.36 (s, 1H), 7.89 (d, J =2.0 Hz, 1H), 7.79 (dd, J = 8.0, 2.0 Hz, 1H), 7.78 (s, 1H), 7.60 (d, J =8.2 Hz, 1H), 2.67 (d, J = 6.6 Hz, 2H), 2.33 (s, 3H), 2.30 (s, 3H), 1.07(s, 6H).

TABLE 11

LCMS Ex. Name −N(R)₂ [M + H]⁺ No. NMR Spectra 274^(B)3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

468.1 ¹H NMR (400 MHz, CD₃OD) δ 7.96 (dd, J = 8.1, 1.9 Hz, 1H), 7.87 (d,J = 1.8 Hz, 1H), 7.76 (s, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.59 (s, 1H),3.54 (s, 2H), 2.30 (s, 3H), 1.75 (s, 6H). 275^(B)3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

482.1 ¹H NMR (400 MHz, CD₃OD) δ 7.98 (dd, J = 8.1, 1.9 Hz, 1H), 7.89 (d,J = 1.8 Hz, 1H), 7.77 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.58 (s, 1H),3.54 (s, 2H), 2.30 (s, 3H), 1.83 − 1.69 (m, 2H), 1.61 − 1.53 (m, 2H),1.52 − 1.42 (m, 2H), 1.28 − 1.11 (m, 2H) 276^(B)3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(3-(cyanomethyl)bicyclo[1.1.1]pentan-1-yl)-4- methylbenzenesulfonamidetrifluoroacetate salt

477.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (s, 1H), 7.87 (dd, J = 8.1, 1.9Hz, 1H), 7.82 (s, 1H), 7.81 (d, J = 1.8 Hz, 1H), 7.70 (br s, 2H), 7.69(d, J = 8.2 Hz, 1H), 7.59 (s, 1H), 2.79 (s, 2H), 2.28 (s, 3H), 1.73 (s,6H) 277^(B) Methyl 3-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenylsulfonamido)bicyclo[1.1.1]pentane-1-carboxylate trifluoroacetate salt

496.1 278^(B) 3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(3-(difluoromethyl)bicyclo[1.1. l]pentan-1-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

488.2 279^(B) 3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methyl-N-(3-(oxazol-5-yl)bicyclo[1.1.1]pentan-1- yl)benzenesulfonamidetrifluoroacetate salt

505.2 ¹H NMR (400 MHz, CD₃OD) δ 8.07 (s, 1H), 7.99 (dd, J = 8.1, 2.0 Hz,1H), 7.90 (d, J = 1.9 Hz, 1H), 7.78 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H),7.59 (s, 1H), 6.86 (s, 1H), 5.51 (s, 1H), 2.31 (s, 3H), 2.19 (s, 6H)280^(B) N-(3-((1H-1,2,4-triazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylbenzenesulfonamide

519.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (s, 1H), 7.90 (s, 1H), 7.82 (dd,J = 8.0, 1.9 Hz, 1H), 7.80 (s, 1H), 7.76 (d, J = 1.7 Hz, 1H), 7.71 (s,2H), 7.65 (d, J = 8.1 Hz, 1H), 7.56 (s, 1H), 4.29 (s, 2H), 2.26 (s, 3H),1.61 (s, 6H) 281^(B)3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4- methylbenzenesulfonamidetrifluoroacetate salt

477.2 282^(B) 3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(3-(2-hydroxypropan-2-yl)bicyclo[1.1.1]pentan-1-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

496.2 ¹H NMR (400 MHz, CD₃OD) δ 8.00 − 7.93 (m, 1H), 7.90 − 7.83 (m,1H), 7.77 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.58 (s, 1H), 2.30 (s, 3H),1.73 (s, 6H), 1.10 (s, 6H) 283^(B)N-(3-((1H-pyrazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

518.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (s, 1H), 7.83 (dd, J = 8.1, 1.9Hz, 1H), 7.80 (s, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.71 (br s, 2H), 7.67(d, J = 8.1 Hz, 1H), 7.58 − 7.50 (m, 2H), 7.37 (d, J = 1.4 Hz, 1H), 6.18(t, J = 2.0 Hz, 1H), 4.19 (s, 2H), 2.26 (s, 3H), 1.59 (s, 6H) 284^(B)N-(3-((1H-imidazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

518.1 ¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (t, J = 1.4 Hz, 1H), 8.74 (s,1H), 7.85 (dd, J = 8.0, 1.9 Hz, 1H), 7.81 (s, 1H), 7.79 (d, J = 1.8 Hz,1H), 7.72 (br s, 2H), 7.69 (d, J = 1.9 Hz, 1H), 7.68 − 7.65 (m, 2H),7.63 (t, J = 1.5 Hz, 1H), 7.57 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 4.35(s, 2H), 2.27 (s, 3H), 1.68 (s, 6H) 285^(B)3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(3-(fluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

456.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (s, 1H), 7.87 (dd, J = 8.1, 1.9Hz, 1H), 7.83 (s, 1H), 7.81 (d, J = 1.7 Hz, 1H), 7.74 − 7.65 (m, 2H),7.59 (s, 1H), 2.27 (s, 3H), 2.09 (d, J = 2.0 Hz, 6H) 286^(B)3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(fluorobicyclo[1.1.1]pentan-1-yl)-4- methylbenzenesulfonamidetrifluoroacetate salt

470.1 ¹H NMR (400 MHz, CD₃OD) δ 7.96 (dd, J = 8.1, 2.0 Hz, 1H), 7.87 (d,J = 2.0 Hz, 1H), 7.76 (s, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.58 (s, 1H),4.37 (d, J = 47.7 Hz, 1H), 2.31 (s, 3H), 1.84 (s, 6H) 287^(B)3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-4- methylbenzenesulfonamide

463.2 ¹H NMR(400 MHz, DMSO-d₆) δ 7.85 (dd, J = 8.1, 1.9 Hz, 1H), 7.83(s, 1H), 7.79 (d, J = 1.7 Hz, 1H), 7.70 (br s, 2H), 7.68 (d, J = 8.3 Hz,1H), 7.61 (s, 1H), 2.26 (s, 3H), 2.25 (s, 6H) 288^(B)3-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenylsulfonamido)bicyclo[1.1.1]pentane-1- carboxamidetrifluoroacetate salt

481.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (s, 1H), 7.87 (dd, J = 8.0, 2.0Hz, 1H), 7.83 (s, 1H), 7.81 (d, J = 1.8 Hz, 1H), 7.70 (br s, 2H), 7.70(d, J = 8.1 Hz, 1H), 7.60 (s, 1H), 7.17 (s, 1H), 6.91 (s, 1H), 2.27 (s,3H), 1.88 (s, 6H) 289^(B)3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methyl-N-(3-(morpholinomethyl)bicyclo[1.1.1]pentan-1-yl)benzenesulfonamide trifluoroacetate salt

537.1 ¹H NMR (400 MHz, CD₃OD) δ 7.97 (dd, J = 8.1, 1.8 Hz, 1H), 7.87 (d,J = 1.5 Hz, 1H), 7.75 (s, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.59 (s, 1H),4.14 − 3.06 (br m, 8H), 3.37 (s, 2H) 2.31 (s, 3H), 2.05 (s, 6H) 290^(B)3-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenylsulfonamido)bicyclo[1.1.1]pentane-1- carboxylic acidtrifluoroacetate salt

482.1 ¹H NMR (400 MHz, CD₃OD) δ 7.97 (dd, J = 8.0, 1.8 Hz, 1H), 7.87 (d,J = 1.5 Hz, 1H), 7.76 (s, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.59 (s, 1H),2.31 (s, 3H), 2.09 (s, 6H) 291^(B)4-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenylsulfonamido)bicyclo[2.1.1]hexane-1- carboxamidetrifluoroacetate salt

495.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (s, 1H), 7.88 (dd, J = 8.1, 1.9Hz, 1H), 7.85 − 7.81 (m, 2H), 7.71 (br s, 2H), 7.68 (d, J = 8.2 Hz, 1H),7.59 (s, 1H), 7.06 (s, 1H), 6.84 (s, 1H), 2.28 (s, 3H), 1.76 − 1.57 (m,6H), 1.39 − 1.25 (m, 2H) 292^(B)N-(3-(1H-Tetrazol-5-yl)bicyclo[1.1.1]pentan-1-yl)-3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

506.3 ¹H NMR (600 MHz, DMSO-d₆) δ 8.75 (br, 1H), 7.91 (dd, J = 8.0, 2.0Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.83 (s, 1H), 7.71 (d, J = 8.1 Hz,1H), 7.70 (br s, 2H), 7.61 (s, 1H), 6.52 (s, 1H), 2.28 (s, 3H), 2.04 (s,6H) 293^(B) 3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methyl-N-(3-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[1.1.1]pentan-1-yl)benzenesulfonamide trifluoroacetate salt

520.0 ¹H NMR (600 MHz, DMSO-d₆) δ 8.96 (s, 1H), 7.91 (dd, J = 8.1, 2.0Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.83 (s, 1H), 7.71 (d, J = 8.2 Hz,1H), 7.69 (br s, 2H), 7.60 (s, 1H), 2.28 (s, 3H), 2.27 (s, 3H), 2.24 (s,6H) 294^(B) 3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methyl-N-(3-(1-methyl-1H-imidazol-2-yl)bicyclo[1.1.1]pentan-1-yl)benzenesulfonamide trifluoroacetate salt

518.1 ¹H NMR (400 MHz, CD₃OD) δ 8.01 (dd, J = 8.1, 1.9 Hz, 1H), 7.91 (d,J = 1.9 Hz, 1H), 7.76 (s, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.59 (s, 1H),7.45 (d, J = 1.9 Hz, 1H), 7.42 (d, J = 1.9 Hz, 1H), 3.82 (s, 3H), 2.51(s, 6H), 2.31 (s, 3H) 295^(B)N-(3-(1,2,4-Oxadiazol-5-yl)bicyclo[1.1.1]pentan-1-yl)-3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

506.0 296^(B) 3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methyl-N-(3-morpholinobicyclo[1.1.l]pentan-1- yl)benzenesulfonamidetrifluoroacetate salt

523.1 ¹H NMR (400 MHz, CD₃OD) δ 7.98 (dd, J = 8.1, 2.0 Hz, 1H), 7.88 (d,J = 2.0 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.59 (s, 1H),3.95 − 3.80 (m, 4H), 3.03 − 2.95 (m, 4H), 2.30 (s, 3H), 2.15 (s, 6H)297^(B) 2-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)-2-azaspiro[3.3]heptan-6-ol

468.2 298^(B) 4-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)-1-methylpiperazin-2-one

469.2 299^(B) 3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-((3S,4S)-4-hydroxy-1-methylpyrrolidin-3-yl)-N,4-dimethylbenzenesulfonamide

485.2 300^(B)3-(5-((2-(3,5-dimethylisoxazol-4-yl)pyrrolidin-1-yl)sulfonyl)-2-methylphenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine

521.1 301^(B) 3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(2-cyanoethyl)-N-cyclohexyl-4-methylbenzenesulfonamide

507.1 302^(B) 3-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)-3-azabicyclo[3.1.0]hexane-1- carbonitrile

463.2 303^(B) 2-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptan- 7-ol 2HCl

469.2 304^(B) 3-(5-((hexahydropyrrolo[3,4-b][1,4]oxazin-4(4aH)-yl)sulfonyl)-2-methylphenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine

483.1 305^(Ex.464) (S)-3-(5-((3-aminopyrrolidin-1-yl)sulfonyl)-2-methylphenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8- aminebis(trifluoroacetate)

441.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.13 ? 7.93 (m, 3H), 7.89? 7.78(m,3H), 7.76 − 7.70 (m, 2H), 7.67 (s, 2H), 3.83 − 3.56 (m, 1H), 3.48 − 3.36(m, 1H), 3.32 (dd, J = 10.7, 6.6 Hz, 1H), 3.24 − 3.08 (m, 2H), 2.29 (s,3H), 2.17 − 1.99 (m, 1H), 1.95 − 1.73 (m, 1H). 306^(Ex.464)3-(5-(((3R,5S)-3-amino-5-methylpiperidin-1-yl)sulfonyl)-2-methylphenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine

469.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.06 − 7.43 (m, 7H), 3.66 (d, J = 6.9Hz, 1H), 3.56 (d, J = 7.9 Hz, 1H), 2.75 − 2.56 (m, 1H), 2.28 (s, 3H),1.84 − 1.69 (m, 3H), 1.69 − 1.36 (m, 3H), 0.81 (d, J = 6.5 Hz, 3H), 0.58(dd, J = 11.8 Hz, 1H). 307^(Ex.464)3-(5-(((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl)sulfonyl)-2-methylphenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine

523.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.09 − 7.39 (m, 7H), 3.80 (d, J = 9.8Hz, 1H), 3.76 − 3.57 (m, 1H), 2.89 − 2.60 (m, 2H), 2.40 − 2.10 (m, 4H),2.08 − 1.85 (m, 2H), 1.85 − 1.41 (m, 2H), 1.17 − 0.77 (m, 1H).308^(Ex.464) 3-(5-(((3S,4R)-3-amino-4-fluoropiperidin-1-yl)sulfonyl)-2-methylphenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine

473.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.17 − 7.21 (m, 7H), 4.64 (d, J = 49.5Hz, 1H), 3.48 − 3.33 (m, 2H), 2.98 − 2.73 (m, 1H), 2.58 − 2.49 (m, 1H),2.39 − 2.30 (m, 1H), 2.28 (s, 3H), 2.08 − 1.62 (m, 4H). 309^(Ex.464)(R)-3-(5-((3-(dimethylamino)piperidin-1-yl)sulfonyl)-2-methylphenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine

483.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 − 7.33 (m, 7H), 3.55 (d, J = 9.9Hz, 1H), 3.43 (d, J = 10.9 Hz, 1H), 2.42 − 2.30 (m, 3H), 2.28 (s, 3H),2.15 (s, 6H), 1.81 − 1.63 (m, 2H), 1.54 − 1.38 (m, 1H), 1.32 − 1.12 (m,1H). 310^(A) 3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

470.1 ¹H NMR (600 MHz, DMSO-d₆) δ 7.85 (dd, J = 8.0, 2.0 Hz, 1H), 7.81(d, J = 2.4 Hz, 2H), 7.69 (br s, 2H), 7.67 − 7.62 (m, 2H) 7.57 (d, J =0.9 Hz, 1H), 4.48 (d, J = 4.2 Hz, 1H), 3.32 − 3.23 (m, 1H), 3.00 − 2.85(m, 1H), 2.25 (s, 3H), 1.70 (br d, J = 9.7 Hz, 2H), 1.61 (br d, J = 10.6Hz, 2H), 1.22 − 1.13 (m, 2H), 1.13 − 1.02 (m, 2H). 311^(A)3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-((3S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-4-methylbenzenesulfonamide

486.2 ¹H NMR (600 MHz, DMSO-d₆) δ 7.87 (dd, J = 8.1, 2.1 Hz, 1H), 7.82(d, J = 2.2 Hz, 1H), 7.82 (s, 1 H) 7.69 (br s, 2H), 7.67 (d, J = 8.2 Hz,1H), 7.62 (s, 1H), 4.56 (br s, 1H), 3.80 − 3.60 (m, 1H), 3.37 − 3.25 (m,1H), 3.25 − 3.18 (m, 1H), 3.16 − 3.07 (m, 1H), 3.05 − 2.93 (m, 2H), 2.26(s, 3H), 1.72 − 1.65 (m, 1H), 1.63 − 1.52 (m, 1H), 1.40 − 1.25 (m, 1H),1.20 − 1.06 (m, 1H). 312^(B)(1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)-3-methylpiperidin-3-yl)methanol

484.1 313^(B) 3-(5-((3-Methoxypiperidin-1-yl)sulfonyl)-2-methylphenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine

470.1 314^(B) 1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidine-3-carbonitrile

465.1

TABLE 12

LCMS Ex. Name −N(R)₂ [M + H]⁺ No. NMR Spectra 315^(B)3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-((3-fluorooxetan-3-yl)methyl)-4- methylbenzenesulfonamidetrifluoroacetate salt

461.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.94 (s, 1H), 8.18 (t, J= 6.5 Hz, 1H), 7.96 (s, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.85 (dd, J =8.1, 1.9 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 4.58 (q, J = 8.3 Hz, 2H),4.53 (q, J = 8.3 Hz, 2H), 3.34 (dd, J = 21.9, 6.5 Hz, 2H), 2.35 (s, 3H)316^(A) 3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-4- methylbenzenesulfonamidetrifluoroacetate salt

459.1 ¹H NMR (500 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.93 (s, 1H), 7.95 (s,1H), 7.94 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 8.1, 2.0 Hz, 1H), 7.82 (t,J = 6.5 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 4.37 (d, J = 10.3 Hz, 2H),4.36 (d, J = 10.2 Hz, 2H), 3.03 (d, J = 6.5 Hz, 2H), 2.34 (s, 3H)317^(A) 3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-(2-hydroxy-2-methylpropyl)-4- methylbenzenesulfonamidetrifluoroacetate salt

445.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.93 (s, 1H), 7.94 (s,1H), 7.91 (d, J = 1.8 Hz, 1H), 7.83 (dd, J = 8.1, 1.9 Hz, 1H), 7.63 (d,J = 8.1 Hz, 1H), 7.50 (t, J = 6.5 Hz, 1H), 2.66 (d, J = 6.6 Hz, 2H),2.33 (s, 3H), 1.06 (s, 6H) 318^(A)3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-((3-methyloxetan-3- yl)methyl)benzenesulfonamidetrifluoroacetate salt

457.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.93 (s, 1H), 7.96 (s,1H), 7.94 (d, J = 2.0 Hz, 1H), 7.90 − 7.81 (m, 2H), 7.66 (d, J = 8.1 Hz,1H), 4.32 (d, J = 5.8 Hz, 2H), 4.16 (d, J = 5..9 Hz, 2H), 2.97 (d, J =6.6 Hz, 2H), 2.36 (s, 3H), 1.19 (s, 3H) 319^(B)3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-4-methylbenzenesulfonamide

469.0 ¹H NMR (500 MHz, DMSO-d₆) δ 8.96 (s, 1H), 8.92 (s, 1H), 8.53 (s,1H), 7.92 (s, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 8.1, 2.0 Hz,1H), 7.64 (d, J = 8.2 Hz, 1H), 3.33 (s, 2H), 2.34 (s, 3H), 1.59 (s, 6H)320^(A) 3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1S,3R)-3-cyanocyclopentyl)-4- methylbenzenesulfonamide (singleenantiomer isolated)

466.1 321^(A)3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1S,3R)-3-cyanocyclopentyl)-4- methylbenzenesulfonamide (singleenantiomer isolated)

466.1 322^(A)3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-methylazetidin-3- yl)benzenesulfonamide

442.1 ¹H NMR (500 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.92 (s, 1H), 8.16 (d, J= 8.3 Hz, 1H), 7.93 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.80 (dd, J =8.1, 2.0 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 3.76 − 3.66 (m, 1H), 3.30 −3.27 (m, 2H), 2.64 − 2.58 (m, 2H), 2.33 (s, 3H), 2.10 (s, 3H). 323^(A)3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1r,3r)-3-(hydroxymethyl)cyclobutyl)-4-methylbenzenesulfonamide trifluoroacetate salt

457.2 ¹H NMR (600 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.93 (s, 1H), 7.96 (d, J= 8.5 Hz, 1H), 7.93 (s, 1H), 7.87 (d, J = 1.7 Hz, 1H), 7.79 (dd, J =8.0, 1.7 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 3.72 (h, J = 8.0 Hz, 1H),3.30 (d, J = 6.7 Hz, 2H), 2.32 (s, 3H), 2.08 (dp, J = 12.6, 6.5 Hz, 1H),1.88 − 1.76 (m, 4H). ¹⁹F NMR (565 MHz, DMSO-d6) δ −69.03 (s), −74.61(s). 324^(B) N-(3-((1H-Imidazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-3-(4-amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

519.1 ¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.98 (s, 1H), 8.94 (s,1H), 8.71 (s, 1H), 7.93 (s, 1H), 7.90 (d, J = 1.9 Hz, 1H), 7.80 (dd, J =8.1, 1.9 Hz, 1H), 7.72 − 7.56 (m, 3H), 4.34 (s, 2H), 2.34 (s, 3H), 1.68(s, 6H) 325^(A)N-((1-Acetyl-3-hydroxyazetidin-3-yl)methyl)-3-(4-amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

500.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.93 (s, 1H), 7.98 −7.80 (m, 4H), 7.65 (d, J = 8.1 Hz, 1H), 5.89 (br s, 1H), 4.03 (d, J =8.7 Hz, 1H), 3.87 − 3.78 (m, 2H), 3.55 (d, J = 9.9 Hz, 1H), 2.95 (d, J =6.3 Hz, 2H), 2.34 (s, 3H), 1.74 (s, 3H) 326^(B)3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-(2-hydroxy-2-methylpropyl)-4- methylbenzenesulfonamidetrifluoroacetate salt

459.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.93 (s, 1H), 7.94 (s,1H), 7.92 (d, J = 1.8 Hz, 1H), 7.84 (dd, J = 8.1, 1.9 Hz, 1H), 7.63 (d,J = 8.2 Hz, 1H), 7.56 (t, J = 6.6 Hz, 1H), 3.02 (s, 3H), 2.77 (d, J =6.6 Hz, 2H), 2.33 (s, 3H), 1.05 (s, 6H) 327^(A)3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-4-methylbenzenesulfonamide trifluoroacetate salt

485.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.96 (s, 1H), 8.92 (s, 1H), 7.93 (s,1H), 7.92 (d, J = 1.9 Hz, 1H), 7.83 (dd, J = 8.1, 2.0 Hz, 1H), 7.62 (d,J = 8.2 Hz, 1H), 7.58 (d, J = 6.9 Hz, 1H), 3.20 − 2.94 (m, 1H), 2.33 (s,3H), 1.69 − 1.54 (m, 2H), 1.55 − 1.36 (m, 2H), 1.34 − 1.16 (m, 4H), 1.05(s, 3H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −69.04 (s), −74.58 (s). 328^(A)3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

483.1 ¹H NMR (400 MHz, CD₃OD) δ 7.97 (d, J = 1.7 Hz, 1H), 7.92 (dd, J =8.1, 1.9 Hz, 1H), 7.82 (s, 1H), 7.60 (d, J = 8.1 Hz, 1H), 3.53 (s, 2H),2.36 (s, 3H), 1.84 − 1.69 (m, 2H), 1.58 − 1.51 (m, 2H), 1.51 − 1.38 (m,2H), 1.26 − 1.16 (m, 2H) 329^(A)3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-(2-hydroxyethyl)azetidin-3-yl)-4- methylbenzenesulfonamidetrifluoroacetate salt

472.1 330^(B)3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-4- methylbenzenesulfonamidetrifluoroacetate salt

464.1 ¹H NMR (400 MHz, CD₃OD) δ 7.98 (d, J = 1.6 Hz, 1H), 7.89 (dd, J =7.9, 1.6 Hz, 1H), 7.85 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 2.41 (s, 3H),2.31 (s, 6H). 331^(B)3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-(3-(fluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

471.1 ¹H NMR (400 MHz, CD₃OD) δ 7.96 (d, J = 1.9 Hz, 1H), 7.90 (dd, J =8.1, 2.0 Hz, 1H), 7.83 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 4.35 (d, J =47.7 Hz, 1H), 2.38 (s, 3H), 1.82 (s, 6H) 332^(B)N-(3-((1H-pyrazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-3-(4-amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

519.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.93 (s, 1H), 8.58 (s,1H), 7.90 (s, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.78 (dd, J = 8.1, 1.9 Hz,1H), 7.62 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.36 (d, J =1.4 Hz, 1H), 6.18 (t, J = 2.0 Hz, 1H), 4.18 (s, 2H), 2.33 (s, 3H), 1.59(s, 6H) 333^(B)3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)-4- methylbenzenesulfonamidetrifluoroacetate salt

457.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.92 (s, 1H), 8.80 (s,1H), 7.95 (s, 1H), 7.92 (d, J = 1.9 Hz, 1H), 7.82 (dd, J = 8.1, 2.0 Hz,1H), 7.66 (d, J = 8.2 Hz, 1H), 2.36 (s, 3H), 2.08 (d, J = 2.4 Hz, 6H)334^(A) 3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-((4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methyl)-4-methylbenzenesulfonamide trifluoroacetate salt

501.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.93 (s, 1H), 7.95 (s,1H), 7.93 − 7.88 (m, 1H), 7.87 − 7.79 (m, 1H), 7.64 (d, J = 8.1 Hz, 1H),7.45 (t, J = 6.5 Hz, 1H), 3.63 − 3.37 (m, 4H), 3.29 (s, 2H), 2.79 (d, J= 6.7 Hz, 2H), 2.34 (s, 3H), 1.39 − 1.26 (m, 4H) 335^(A)3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-((3-hydroxyazetidin-3-yl)methyl)-4- methylbenzenesulfonamidetrifluoroacetate salt

458.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.96 (s, 1H), 8.80 (brs, 1H), 8.66 (br s, 1H), 8.00 (t, J = 6.8 Hz, 1H), 7.95 (s, 1H), 7.93(d, J = 1.4 Hz, 1H), 7.86 (dd, J = 8.0, 1.8 Hz, 1H), 7.67 (d, J = 8.0Hz, 1H), 6.26 (s, 1H), 3.99 − 3.86 (m, 2H), 3.84 − 3.69 (m, 2H), 3.01(d, J = 6.5 Hz, 2H), 2.34 (s, 3H) 336^(B)3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin- −NH₂ 373.17-yl)-4-methylbenzenesulfonamide trifluoroacetate salt ¹H NMR (400 MHz,DMSO-d₆ containing CD₃OD) δ 7.90 (d, J = 1.8 Hz, 1H), 7.86 (dd, J = 7.7,2.2 Hz, 1H), 7.86 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 2.26 (s, 3H)337^(A) 3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-(oxetan-3-yl)azetidin-3-yl) benzenesulfonamidetrifluoroacetate salt

484.1 338^(B)N-(3-((1H-1,2,4-triazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-3-(4-amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonamide

520.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (br s, 2H), 8.38 (s, 1H) 7.91 (s,1H), 7.90 (s, 1H), 7.88 (d, J = 1.9 Hz, 1H), 7.78 (dd, J = 8.1, 1.9 Hz,1H), 7.62 (d, J = 8.2 Hz, 1H), 4.28 (s, 2H), 2.34 (s, 3H), 1.62 (s, 6H)339^(B) 3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

489.1 ¹H NMR (400 MHz, CD₃OD) δ 7.97 (d, J = 2.0 Hz, 1H), 7.90 (dd, J =8.1, 2.0 Hz, 1H), 7.83 (s, 1H), 7.63 (d, J = 8.1 Hz, 1H), 5.81 (t, J =56.4 Hz, 1H), 2.38 (s, 3H), 1.91 (s, 6H) 340^(B)3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(3-morpholinobicyclo[1.1.1]pentan-1-yl)benzenesulfonamide trifluoroacetate salt

524.1 341^(B)3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-(3-aminobicyclo[1.1.1]pentan-1-yl)-4- methylbenzenesulfonamidetrifluoroacetate salt

454.1 ¹H NMR (400 MHz, CD₃OD) δ 7.97 (d, J = 2.0 Hz, 1H), 7.91 (dd, J =8.1, 2.0 Hz, 1H), 7.83 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 2.38 (s, 3H),2.15 (s, 6H) 342^(B) 1-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-3-cyclopropylazetidin-3-ol TFA

469.1 343^(B) 2-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-2-azaspiro[3.3]heptan-6-ol TFA

469.1 344^(B)3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(2-cyanoethyl)-N,4-dimethylbenzenesulfonamide

440.2 345^(B)3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(2-cyanoethyl)-N-cyclopropyl-4- methylbenzenesulfonamide

466.2 346^(B)3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(2-cyanoethyl)-N-cyclopentyl-4-methylbenzenesulfonamide

494.2 347^(B)(S)-(1-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)pyrrolidin-2-yl)methanol

457.2 348^(B) 2-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-6-methyl-2,6-diazaspiro[3.4]octan-5-one

496.2 349^(B) 2-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-7-ol

498.2 350^(B) 2-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-5-isopropyl-2,5-diazabicyclo[2.2.1]heptan-7-ol

512.2 351^(B) 3-(5-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-7-hydroxy-2,5-diazabicyclo[2.2.1]heptan-2-yl)cyclopentane-1-carbonitrile

563.2 352^(B) 2-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-7-ol

484.2 353^(B) 2-(5-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-7-hydroxy-2,5-diazabicyclo[2.2.1]heptan-2-yl)cyclopentane-1-carbonitrile

563.2 354^(B) 3-(5-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-7-hydroxy-2,5-diazabicyclo[2.2.1]heptan-2-yl)cyclobutane-1- carbonitrile

549.2 355^(B) 2-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptan-7-ol

470.1 356^(A)3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-((3S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-4-methylbenzenesulfonamide

487.1 ¹H NMR (400 MHz, DMSO) δ 8.70 (br s, 2H), 7.97 − 7.85 (m, 2H),7.82 (dd, J = 8.1, 1.9 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 4.66 − 4.41(m, 1H), 3.77 − 3.55 (m, 1H), 3.28 − 3.23 (m, 1H), 3.24 − 3.15 (m, 1H),3.15 − 3.06 (m, 1H), 3.03 − 2.92 (m, 2H), 2.32 (s, 3H), 1.75 − 1.62 (m,1H), 1.62 − 1.47 (m, 1H), 1.40 − 1.20 (m, 1H), 1.20 − 1.00 (m, 1H).357^(B) 3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-((1-methyl-1H-pyrazol-5- yl)methyl)benzenesulfonamide

467.2 358^(B)3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-(pyrazin-2-ylmethyl)benzenesulfonamide

465.1

TABLE 13

LCMS Ex. Name −N(R)₂ R′ = [M + H]⁺ No. ¹H NMR 359^(A)5-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-2-fluoro-N- ((lr,40-4-hydroxy-4-methylcyclohexyl)benzenesulfonamide

4-F 420.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (s, 1H), 7.98 − 7.90 (m, 2H),7.79 (s, 1H), 7.68 (d, J = 4.6 Hz, 1H), 7.61 (dd, J = 9.5 Hz, 1H), 7.30(d, J = 4.7 Hz, 1H), 7.01 (s, 2H), 4.13 (s, 1H), 3.27 − 3.19 (m, 1H),1.68 − 1.56 (m, 2H), 1.55 − 1.43 (m, 2H), 1.38 − 1.19 (m, 4H), 1.05 (s,3H). 360^(A) 5-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-2-fluoro-N-((4-(hydroxymethyl)tetrahydro-2H-pyran-4- yl)methyl)benzenesulfonamide

4-F 436.1 ¹H NMR (600 MHz, DMSO-d₆) δ 7.99 − 7.92 (m, 2H), 7.79 (s, 1H),7.71 (d, J = 4.7 Hz, 1H), 7.66 − 7.59 (m, 1H), 7.30 (d, J = 4.7 Hz, 1H),7.02 (s, 2H), 3.48 (dd, J = 5.5, 5.5 Hz, 4H), 3.29 (s, 2H), 2.95 (s,2H), 1.42 − 1.26 (m, 4H). 361^(A)5-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-N-(2- hydroxy-2-methylpropyl)-2,4-dimethylbenzenesulfonamide

2,4- diMe 390.1 ¹H NMR (400 MHz, DMSO-d₆) δ 7.72 (s, 1H), 7.63 (s 1H),7.54 (br s, 1H), 7.46 (s, 1H), 7.26 − 7.17 (m, 2H), 6.99 (s, 2H), 4.36(s, 1H), 2.71 (s, 2H), 2.62 (s, 3H), 2.18 (s, 3H), 1.02 (s, 6H).

TABLE 14

LCMS Ex. Name −N(R)₂ R′ = [M + H]⁺ No. NMR Spectra 362^(B)3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.2.1]heptan-1-yl)-4-(methyl- d₃)benzenesulfonamidetrifluoroacetate salt

2-CD₃ 427.2 ¹H NMR (400 MHz, CD₃OD δ 8.13 (s, 1H), 8.03 (d, J = 2.0 Hz,1H), 7.90 (dd, J = 8.1, 2.1 Hz, 1H), 7.80 (s, 1H), 7.61 (d, J = 8.1 Hz,1H), 2.05 − 1.95 (m, 2H), 1.94 (s, 2H), 1.90 − 1.76 (m, 4H), 1.70 − 1.57(m, 2H) 363^(A) 5-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-2,4- dimethylbenzenesulfonamide

 2-CH₃, 4-CH₃ 429.1 ¹H NMR (500 MHz, CD₃OD) δ 8.08 (s, 1H), 8.06 (s,1H), 7.70 (s, 1H), 7.40 (s, 1H) 3.53 (s, 2H), 2.70 (s, 3H), 2.34 (s,3H), 1.80 − 1.72 (m, 2H), 1.57 − 1.51 (m, 2H), 1.51 − 1.39 (m, 2H), 1.27− 1.17 (m, 2H) 364^(A)3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide trifluoroacetate salt

— 396.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (s, 1H), 8.71 − 8.64 (m, 1H),8.38 (s, 1H), 8.37 − 8.29 (m, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 8.18 (s,1H), 7.87 − 7.80 (m, 1H), 7.74 (t, J = 7.8 Hz, 1H), 2.05 − 1.96 (m, 2H),1.92 − 1.84 (m, 2H), 1.77 − 1.69 (m, 2H), 1.65 − 1.58 (m, 2H) 365^(A)5-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-2- fluorobenzenesulfonamidetrifluoroacetate salt

4-F 414.1 ¹H NMR (400 MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.68 (dd, J = 7.0,2.1 Hz, 1H), 8.40 − 8.33 (m, 2H), 8.30 (s, 1H), 8.22 (s, 1H), 8.17 (s,1H), 7.66 ? 7.56 (m, 1H), 2.09 − 2 01 (m, 2H), 1.93 − 1.85 (m, 2H), 1.78− 1.71 (m, 2H), 1.71 − 1.64 (m, 2H) 366^(A)5-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-2-fluoro-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1- yl)benzenesulfonamidetrifluoroacetate salt

4-F 419.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (s, 1H), 8.66 (dd, J = 6.9,2.0 Hz, 1H), 8.41 − 8.33 (m, 2H), 8.31 (s, 1H), 8.22 (s, 1H), 8.15 (s,1H), 7.59 (t, J = 9.4 Hz, 1H), 3.33 (s, 2H), 1.74 − 1.66 (m, 2H), 1.51 −1.44 (m, 2H), 1.40 − 1.31 (m, 2H), 1.12 − 1.04 (m, 2H) 367^(A)5-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-2-chloro-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1- yl)benzenesulfonamidetrifluoroacetate salt

4-Cl 435.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (d, J = 2.1 Hz, 1H), 8.64(s, 1H), 8.37 (s, 1H), 8.34 − 8.27 (m, 2H), 8.22 (s, 1H), 8.19 (s, 1H),7.78 (d, J = 8.4 Hz, 1H), 3.32 (s, 2H), 1.75 − 1.67 (m, 2H), 1.50 − 1.43(m, 2H), 1.37 − 1.28 (m, 2H), 1.11 − 1.02 (m, 2H) 368^(A)3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1- yl)benzenesulfonamidetrifluoroacetate salt

— 401.1 ¹H NMR (400 MHz, CD₃OD) δ 8.75 (s, 1H), 8.32 (d, J = 7.7 Hz,1H), 8.20 (s, 1H), 8.06 (s, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.70 (t, J =7.9 Hz, 1H), 3.52 (s, 2H), 1.86 − 1.77 (m, 2H), 1.61 − 1.53 (m, 2H),1.51 − 1.43 (m, 2H), 1.27 − 1.19 (m, 2H) 369^(B)5-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-2- methylbenzenesulfonamidetrifluoroacetate salt

4-CH₃ 410.1 ¹H NMR (600 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.71 (d, J = 1.7Hz, 1H), 8.34 (s, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 8.17 (dd, J = 7.9,1.8 Hz, 1H), 8.12 (s, 1H), 7.55 (d, J = 8.1 Hz, 1H), 2.64 (s, 2H), 2.07− 1.98 (m, 2H), 1.91 − 1.84 (m, 2H), 1.78 − 1.68 (m, 2H), 1.68 − 1.60(m, 2H) 370^(B) 3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1r,3r)-3-cyanocyclobutyl)-4-(methyl- d₃)benzenesulfonamidetrifluoroacetate salt

2-CD₃ 387.1 ¹H NMR (400 MHz, CD₃OD) δ 8.18 (s, 1H), 8.00 (d, J = 1.9 Hz,1H), 7.86 (dd, J = 8.1, 2.0 Hz, 1H), 7.81 (s, 1H), 7.62 (d, J = 8.1 Hz,1H), 4.13 (p, J = 7.7 Hz, 1H), 3.09 (ttd, J = 9.7, 3.7, 1.5 Hz, 1H),2.54 − 2.43 (m, 2H), 2.35 − 2.22 (m, 2H) 371^(B)3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(isocyanomethyl)bicyclo[1.1.1]pentan-1-yl)-4-(methyl-d₃)benzenesulfonamide trifluoroacetate salt

2-CD₃ 413.2 ¹H NMR (400 MHz, CD₃OD δ 8.14 (s, 1H), 8.00 (d, J = 2.0 Hz,1H), 7.88 (dd, J = 8.1, 2.0 Hz, 1H), 7.79 (s, 1H), 7.62 (d, J = 8.1 Hz,1H), 2.73 (s, 2H), 1.88 (s, 6H) 372^(A)3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4- methoxybenzenesulfonamidetrifluoroacetate salt

2-OMe 426.1 ¹H NMR (400 MHz, CD₃OD) δ 8.66 (d, J = 2.4 Hz, 1H), 8.18 (s,1H), 8.04 (s, 1H), 7.95 (dd, J = 8.9, 2.4 Hz, 1H), 7.37 (d, J = 8.8 Hz,1H), 4.03 (s, 3H), 2.21 − 2.09 (m, 2H), 1.99 − 1.90 (m, 2H), 1.90 − 1.77(m, 2H), 1.73 − 1.58 (m, 2H) 373^(A)3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4- (trifluoromethoxy)benzenesulfonamidetrifluoroacetate salt

2- OCF₃ 480.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (s, 1H), 8.54 (d, J = 2.0Hz, 1H), 8.43 (s, 1H), 8.37 (s, 1H), 8.17 (s, 1H), 8.01 (dd, J = 8.6,1.8 Hz, 1H), 7.93 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 2.09 − 1.96 (m,2H), 1.96 − 1.84 (m, 2H), 1.81 − 1.69 (m, 2H), 1.69 − 1.59 (m, 2H)374^(B) 3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-hydroxybicyclo[2.1.1]hexan-1-yl)-4-(methyl- d3)benzenesulfonamide

2-CD₃ 404.2 ¹H NMR (400 MHz, CD₃OD) δ 8.08 (s, 1H), 8.00 (d, J = 1.9 Hz,1H), 7.88 (dd, J = 8.1, 2.1 Hz, 1H), 7.74 (s, 1H), 7.59 (d, J = 8.1 Hz,1H), 4.59 (s, 1H), 1.81 − 1.70 (m, 2H), 1.66 − 1.55 (m, 4H), 1.55 − 1.49(m, 2H) 375^(A) 3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-5-fluoro-N-(1-(hydroxymethyl)-2- oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

2-CH₃ 3-F 463.1 376^(A) 5-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-2-fluoro-N-((1r,4r)-4-hydroxy-4- methylcyclohexyl)benzenesulfonamide

4-F 421.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (dd, J = 6.9, 2.1 Hz, 1H),8.39 − 8.22 (m, 3H), 8.19 (s, 1H), 8.13 (s, 1H), 7.98 (br s, 1H), 7.57(dd, J = 9.4, 9.4 Hz, 1H), 4.12 (s, 1H), 3.25 − 3.12 (m, 1H), 1.68 −1.56 (m, 2H), 1.54 − 1.43 (m, 2H), 1.39 − 1.18 (m, 4H), 1.04 (s, 3H).377^(A) 5-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-2-chloro-N-((1r,4r)-4-hydroxy-4- methylcyclohexyl)benzenesulfonamide

4-Cl 437.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (d, J = 2.0 Hz, 1H), 8.41 −8.24 (m, 3H), 8.19 (d, J = 7.3 Hz, 2H), 7.88 (br s, 1H), 7.77 (d, J =8.4 Hz, 1H), 4.11 (s, 1H), 3.21 − 3.06 (m, 1H), 1.66 − 1.56 (m, 2H),1.55 − 1.44 (m, 2H), 1.43 − 1.29 (m, 2H), 1.29 − 1.13 (m, 2H), 1.05 (s,3H).

TABLE 15

LCMS Ex. Name —N(R)₂ R′ = [M + H]⁺ No. NMR Spectra 378^(B)3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-(3-(isocyanomethyl)bicyclo[1.1.1]pentan-1-yl)-4-(methyl-d₃)benzenesulfonamide trifluoroacetate salt

2-CD₃ 426.2 ¹H NMR (400 MHz, CD₃OD) δ 7.98 (dd, J = 8.1, 2.0 Hz 1H),7.86 (d, J = 1.9 Hz, 1H), 7.82 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H),7.22-7.16 (m, 1H), 2.73 (s, 2H), 2.34 (d, J = 0.9 Hz, 3H) 1.88 (s, 6H)379^(B) 3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl- d₃)benzenesulfonamidetrifluoroacetate salt

2-CD₃ 426.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (s, 1H), 7.91 (dd, J = 8.1,2.0 Hz, 1H), 7.86 (s, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 8.1Hz, 1H), 7.21 (s, 1H), 2.23 (s, 3H), 2.02-1.93 (m, 2H), 1.93-1.81 (m,2H), 1.74-1.65 (m, 2H), 1.65-1.54 (m, 2H) 380^(A)5-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-(4-cyanobicyclo[2.1.1]hexan-l-yl)-2- fluorobenzenesulfonamidetrifluoroacetate salt

4-F 427.1 1H NMR (400 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.07 (s, 1H),8.04-7.96 (m, 2H), 7.77- 7.65 (m, 2H), 2.29 (s, 3H), 2.08-1.98 (m, 2H),1.93-1.84 (m, 2H), 1.74-1.68 (m, 2H), 1.68-1.60 (m, 2H) 381^(A)3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1- yl)benzenesulfonamide

— 414.1 ¹H NMR (400 MHz, CD₃OD) δ 8.11 (t, J = 1.4 Hz, 1H), 8.03-7.94(m, 1H), 7.93- 7.84 (m, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.74 (s, 1H),7.61 (s, 1H), 3.53 (s, 2H), 2.31 (s, 3H), 1.85-1.66 (m, 2H), 1.66-1.53(m, 2H), 1.53-1.42 (m, 2H), 1.28-1.14 (m, 2H) 382^(B)5-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2- fluorobenzenesulfonamidetrifluoroacetate salt

4-F 413.1 ¹H NMR (600 MHz, DMSO-d₆) δ 9.44 (s, 1H), 8.06 -7.89 (m, 3H),7.70 (t, J = 9.3 Hz, 1H), 7.65 (s, 1H), 2.29 (s, 6H), 2.27 (s, 3H)383^(B) 3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamide trifluoroacetate salt

2-CD₃ 431.1 ¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.40 (s, 1H), 7.90(dd, J = 8.3, 2.1 Hz, 1H),7.89 (s, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.68(d, J = 8.1 Hz, 1H), 7.19 (s, 1H), 3.35 (s, 2H), 2.24 (s, 3H), 1.76-1.58(m, 2H), 1.45-1.38 (m, 2H), 1.38-1.32 (m, 2H), 1.08-0.99 (m, 2H) 384^(B)3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-(4-hydroxybicyclo[2.1.1]hexan-1-yl)-4-(methyl- d₃)benzenesulfonamide

2-CD₃ 417.2 385^(A) 5-(8-amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-2-chloro-N-((1r,4r)-4-hydroxy-4- methylcyclohexyl)benzenesulfonamide

4-C1 450.1 ¹H NMR (600 MHz, DMSO-d₆) δ 8.12 (d, J = 2.2 Hz, 1H), 7.93(s, 1H), 7.89 (dd, J = 8.2, 2.2 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.78(s, 1H), 7.58 (d, J = 0.9 Hz, 1H), 7.00 (s, 2H), 4.13 (s, 1H), 3.25-3.14(m, 1H), 2.20 (s, 3H), 1.66-1.57 (m, 2H), 1.55-1.47 (m, 2H), 1.40-1.30(m, 2H), 1.29-1.23 (m, 2H), 1.05 (s, 3H).

TABLE 16

LCMS Ex. Name —N(R)₂ R′ = [M + H]⁺ No. NMR Spectra 386^(B)3-(4-Amino-2-methylimidazo[2,1-ƒ][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1] hexan-1-yl)-4-(methyl-d₃)benzenesulfonamide trifluoroacetate salt

2-CD₃ 427.3 ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (s, 1H), 8.24 (s, 1H), 8.16(s, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.80 (dd, J = 8.1, 2.1 Hz, 1H), 7.76(s, 1H), 7.62 (d, J = 8.1 Hz, 1H), 2.29 (s, 3H), 2.02- 1.93 (m, 2H),1.93-1.84 (m, 2H), 1.77-1.67 (m, 2H), 1.61 (m, 2H) 387^(A)5-(4-Amino-2-methylimidazo[1,2-ƒ][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-2-fluorobenzenesulfonamide trifluoroacetate salt

4-F 428.1 ¹H NMR (400 MHz, DMSO-d₆) δ 9.13 (s, 1H), 8.72 (dd, J = 7.1,2.1 Hz, 1H), 8.35 (ddd, J = 8.1, 4.2, 2.0 Hz, 1H), 8.26 (s, 1H), 8.20(s, 1H), 8.10 (s, 1H), 7.61 (t, J = 9.4 Hz, 1H), 2.39 (s, 3H), 2.11-1.99(m, 2H), 1.93-1.79 (m, 2H), 1.79-1.69 (m, 2H), 1.69-1.58 (m, 2H) 388^(B)5-(4-Amino-2-methylimidazo[1,2-ƒ][1,2,4] triazin-7-yl)-N-(3-cyanobicyclo[1.1.l] pentan-1-yl)-2-fluorobenzenesulfonamide trifluoroacetate salt

4-F 414.1 ¹H NMR (400 MHz, CD₃OD) δ 8.74 (dd, J = 6.9, 2.1 Hz, 1H), 8.32(ddd, J = 8.2, 4.5, 2.2 Hz, 1H), 7.97 (s, 1H), 7.48 (t, J = 9.3 Hz, 1H),2.50 (s, 3H), 2.37 (s, 6H) 389^(A)5-(4-amino-2-methylimidazo[2,1-f][1,2,4]triazin-7-yl)-2-chloro-N-((3S,6R)-6-(cyanomethyl)tetrahydro-2H-pyran-3-yl)- 4-methylbenzenesulfonamide

2-Me, 4-C1 476.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.29-7.96 (m, 4H), 7.77 (s,1H), 7.73 (s, 1H), 3.72 (d, J = 8.2 Hz, 1H), 3.49-3.38 (m, 1H),3.20-3.00 (m, 2H), 2.77-2.63 (m, 1H), 2.57 (dd, J = 17.1, 6.5 Hz, 1H),2.34 (s, 3H), 2.27 (s, 3H), 1.81-1.71 (m, 1H), 1.71-1.60 (m, 1H), 1.59-1.36 (m, 1H), 1.35-1.14 (m, 1H).

TABLE 17

LCMS Ex. Name —N(R)₂ R′ = [M + H]⁺ No. NMR Spectra 390^(B)3-(8-Amino-6-(trifluoromethyl) imidazo[1,2-a]pyrazin-3-yl)-N-(4-(hydroxymethyl)bicyclo [2.1.1]hexan-1-yl)-4-(methyl-d₃)benzenesulfonamide trifluoroacetate salt

2-CD₃ 485.1 ¹H NMR (400 MHz, CD₃OD) δ 7.98 (dd, J = 8.1, 2.0 Hz, 1H),7.89 (d, J = 2.0 Hz, 1H), 7.77 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.58(s, 1H), 3.54 (s, 2H), 1.81-1.71 (m, 2H), 1.61-1.52 (m, 2H), 1.52-1.43(m, 2H), 1.27-1.15 (m, 2H) 391^(B) 3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N- (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-4-(methyl-d₃) benzenesulfonamide trifluoroacetatesalt

2-CD₃ 471.1 ¹H NMR (400 MHz, CD₃OD) δ 7.96 (dd, J = 8.1, 2.0 Hz, 1H),7.87 (d, J = 1.9 Hz, 1H), 7.77 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.59(s, 1H), 3.54 (s, 2H), 1.75 (s, 6H) 392^(A)5-(8-Amino-6-(trifluoromethyl) imidazo[1,2-a]pyrazin-3-yl)-2-chloro-N-(4-cyanobicyclo[2.1.1] hexan-1-yl)benzenesulfonamidetrifluoroacetate salt

4-C1 497.1 ¹H NMR (400 MHz, CD₃OD) δ 8.34 (d, J = 2.0 Hz, 1H), 8.08 (s,1H), 7.91 (dd, J = 8.2, 2.1 Hz, 1H), 7.89 (s, 1H), 7.84 (d, J = 8.3 Hz,1H), 2.16-2.06 (m, 2H), 2.01-1.90 (m, 2H), 1.88 -1.79 (m, 2H), 1.75-1.67(m, 2H) 393^(B) 3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4- chloro-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl) benzenesulfonamide

2-C1 502.1 ¹H NMR (400 MHz, CD₃OD) δ 8.08-8.01 (m, 2H), 7.89 (d, 1H),7.82 (s, 1H), 7.69 (s, 1H), 3.55 (s, 2H), 1.85-1.72 (m, 2H), 1.62-1.56(m, 2H), 1.54-1.48 (m, 2H), 1.29-1.19 (m, 2H) 394^(A)3-(8-Amino-6-(trifluoromethyl) imidazo[1,2-a]pyrazin-3-yl)-N-(4-(hydroxymethyl)bicyclo [2.1.1]hexan-1-yl) benzenesulfonamidetrifluoroacetate salt

— 468.1 395^(A) 3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N- (4-cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide trifluoroacetate salt

— 463.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (s, 1H), 8.10-8.06 (m, 1H),8.04 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.96-7.91 (m, 2H), 7.81 (t, J =7.8 Hz, 1H), 7.70 (s, 2H), 2.04-1.94 (m, 2H), 1.92-1.84 (m, 2H),1.75-1.67 (m, 2H), 1.66-1.56 (m, 2H) 396^(A)5-(8-Amino-6-(trifluoromethyl) imidazo[1,2-a]pyrazin-3-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1- yl)-2-fluorobenzenesulfonamidetrifluoroacetate salt

4-F 481.1 ¹H NMR (400 MHz, CD₃OD) δ 8.14 (dd, J = 6.7, 2.1 Hz, 1H), 8.04(s, 1H), 8.01-7.92 (m, 1H), 7.85 (s, 1H), 7.58 (t, J = 9.3 Hz, 1H),2.19-2.10 (m, 2H), 2.02-1.93 (m, 2H), 1.89- 1.80 (m, 2H), 1.77-1.70 (m,2H) 397^(A) 3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N- (4-cyanobicyclo[2.1.1]hexan-1-yl)-5-fluoro-4- methylbenzenesulfonamide trifluoroacetate salt

2-CH₃, 3-F 495.0 398^(A) 5-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-2- fluoro-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl) benzenesulfonamide trifluoroacetate salt

4-F 486.0 ¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (s, 1H), 8.05-7.95 (m, 3H),7.90 (s, 1H), 7.74- 7.56 (m, 3H), 3.34 (s, 2H), 1.74-1.63 (m, 2H),1.49-1.41 (m, 2H), 1.40-1.29 (m, 2H), 1.12-1.03 (m, 2H) 399^(A)5-(8-Amino-6-(trifluoromethyl) imidazo[1,2-a]pyrazin-3-yl)-2-chloro-N-(4-(hydroxymethyl) bicyclo[2.1.1]hexan-1-yl) benzenesulfonamidetrifluoroacetate salt

4-C1 502.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (s, 1H), 8.20 (d, J = 1.9Hz, 1H), 8.03 (s, 1H), 7.98- 7.92 (m, 2H), 7.85 (d, J = 8.3 Hz, 1H),7.70 (s, 2H), 3.33 (s, 2H), 1.73-1.63 (m, 2H), 1.48- 1.40 (m, 2H), 1.38-1.30 (m, 2H), 1.13-1.03 (m, 2H) 400^(A) 5-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N- (4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-2,4- dimethylbenzenesulfonamide trifluoroacetate salt

2-CH₃, 4-CH₃ 496.1 ¹H NMR (400 MHz, CD₃OD) δ 7.93 (s, 1H), 7.73 (s, 1H),7.57 (s, 1H), 7.50 (s, 1H), 3.53 (s, 2H), 2.74 (s, 3H), 2.25 (s, 3H),1.81-1.69 (m, 2H), 1.60-1.51 (m, 2H), 1.51-1.42 (m, 2H), 1.28-1.16 (m,2H) 401^(B,Ex. 260) 3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4- cyano-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl) benzenesulfonamide trifluoroacetate salt

2-CN 493.1 ¹H NMR (600 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.31 (d, J = 8.2Hz, 1H), 8.17 (d, J = 1.7 Hz, 1H), 8.08 (dd, J = 8.2, 1.8 Hz, 1H), 8.03(s, 1H), 7.97 (s, 1H), 7.78 (s, 2H), 3.36 (s, 2H), 1.71-1.63 (m, 2H),1.47-1.40 (m, 2H), 1.40-1.33 (m, 2H), 1.14-1.05 (m, 2H) 402^(A)5-(4-amino-2-methylimidazo [1,2-ƒ][1,2,4]triazin-7-yl)-2-fluoro-N-((lr,4r)-4-hydroxy- 4-methylcyclohexyl)-4-methylbenzenesulfonamide trifluoroacetate salt

2-CH₃4-F 449.1 ¹H NMR (400 MHz, CD₃CN) δ 7.96 (d, J = 7.6 Hz, 1H), 7.62(s, 1H), 7.34 (d, J = 11.2 Hz, 1H), 5.85 (d, J = 7.6 Hz, 1H), 3.33 (s,1H), 2.41 (s, 1H), 2.35 (s, 3H), 2.17 (s, 3H), 1.82- 1.69 (m, 2H),1.63-1.51 (m, 2H), 1.48-1.31 (m, 4H), 1.16 (s, 3H). 403^(A)5-(4-amino-2-methylimidazo [1,2-ƒ][1,2,4]triazin-7-yl)-2-chloro-N-(2-hydroxy-2- methylpropyl)-4- methylbenzenesulfonamidetrifluoroacetate salt

2-CH₃ 4-C1 425.1 404^(A) 3-(4-amino-2-methylimidazo[1,2-ƒ][1,2,4]triazin-7-yl)-5- fluoro-N-(1-(hydroxymethyl)-2-oxabicyclo[2.2.2]octan-4-yl)-4- methylbenzenesulfonamidetrifluoroacetate salt

2- CH₃ 3-F 477.2 405^(A) 5-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N- ((3S,6R)-6-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-2- fluoro-4-methylbenzenesulfonamidetrifluoroacetate salt

2-Me 4-F 513.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (d, J = 7.2 Hz, 1H),7.82-7.74 (m, 2H), 7.70 (s, 1H), 7.65 (br s, 2H), 7.58 (d, J = 11.3 Hz,1H), 3.82-3.64 (m, 1H), 3.57-3.37 (m, 1H), 3.25-3.04 (m, 2H), 2.71 (dd,J = 17.0, 4.4 Hz, 1H), 2.59 (dd, J = 17.0, 6.7 Hz, 1H), 2.20 (s, 3H),1.82-1.72 (m, 1H), 1.72-1.62 (m, 1H), 1.55-1.37 (m, 1H), 1.36-1.17 (m,1H). 406^(B) 3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N- ((3S,6R)-6-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-4- (methyl-d₃)benzenesulfonamide

2-CD₃ 498.2 ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (d, J = 7.8 Hz, 1H),7.84-7.77 (m, 2H), 7.70-7.57 (m, 3H), 3.71 (d, J = 8.9 Hz, 1H),3.50-3.38 (m, 1H), 3.17-2.94 (m, 2H), 2.70 (dd, J = 17.0, 4.0 Hz, 1H),2.57 (dd, J = 17.0, 6.6 Hz, 1H), 1.76-1.67 (m, 1H), 1.67-1.58 (m, 1H),1.46-1.31 (m, 1H), 1.31-1.14 (m, 1H). 407^(A)3-(8-amino-6-(trifluoromethyl) imidazo[1,2-a]pyrazin-3-yl)-N-(2-hydroxy-2-methylpropyl)-4- (trifluoromethyl) benzenesulfonamide

2-CF₃ 498.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.27-8.10 (m, 2H), 8.05 (s, 1H),7.90-7.59 (m, 5H), 4.39 (s, 1H), 2.73 (s, 2H), 1.03 (s, 6H). 408^(A)(1-((5-(8-Amino-6- (trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-2-fluoro-4- methylphenyl)sulfonyl)piperidin-3-yl)methanol

2-Me 4-F 488.1 ¹H NMR (400 MHz, DMSO-d₆) δ 7.80 (s, 1H), 7.75 (s, 1H),7.73 (d, J = 7.1 Hz, 1H), 7.65 (br s, 2H), 7.63 (d, J = 11.4 Hz, 1H),4.57 (t, J = 5.2 Hz, 1H), 3.71 (d, J = 9.1 Hz, 1H), 3.57 (d, J = 11.4Hz, 1H), 3.36-3.26 (m, 1H), 3.22-3.10 (m, 1H), 2.61-2.42 (m, 1H), 2.32(t, J =10.7 Hz, 1H), 2.25 (s, 3H), 1.78-1.55 (m, 3H), 1.55-1.37 (m, 1H),0.99 (q, J = 11.6 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −66.62, −108.29.409^(B) (1-((3-(8-Amino-6- (trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-(methyl- d₃)phenyl)sulfonyl)piperidin- 3-yl)methanol

2-CD₃ 473.1

TABLE 18

LCMS Ex. Name —N(R)₂ R′ = [M + H]⁺ No. NMR Spectra 410^(A)5-(4-Amino-2-(trifluoromethyl)imidazo[1,2-ƒ][1,2,4]triazin-7-yl)-2-chloro-N-((lr,4r)-4-hydroxy-4-methylcyclohexyl)-4- methylbenzenesulfonamide trifluoroacetatesalt

2-CH₃, 4-C1 519.1 ¹H NMR (600 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.93 (s,1H), 8.14 (s, 1H), 7.99 (s, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.75 (s, 1H),3.18-3.08 (m, 1H), 2.37 (s, 3H), 1.64-1.54 (m, 2H), 1.54-1.48 (m, 2H),1.38-1.29 (m, 2H), 1.29-1.18 (m, 2H), 1.06 (s, 3H). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −69.12 (s), −74.96 (s). 411^(A)3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-ƒ][1,2,4]triazin-7-yl)-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)benzenesulfonamide trifluoroacetate salt

— 469.1 ¹H NMR (400 MHz, CD₃OD) δ 8.68-8.64 (m, 1H), 8.37-8.31 (m, 1H),8.14 (s, 1H), 7.97-7.90 (m, 1H), 7.72 (t, J = 7.9 Hz, 1H), 3.51 (s, 2H),1.87-1.72 (m, 2H), 1.59- 1.50 (m, 2H), 1.50-1.41 (m, 2H), 1.28-1.15 (m,2H) 412^(A) 5-(4-Amino-2-(trifluoromethyl)imidazo[1,2-ƒ][1,2,4]triazin-7-yl)-2-fluoro-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-4- methylbenzenesulfonamide trifluoroacetatesalt

2-CH₃, 4-F 503.0 ¹H NMR (600 MHz, DMSO-d₆) δ 8.96 (s, 1H), 8.92 (s, 1H),7.94 (s, 1H), 7.92 (d, J = 7.4 Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.54(d, J = 11.2 Hz, 1H), 3.23-3.09 (m, 1H), 2.34 (s, 3H), 1.67-1.56 (m,2H), 1.56-1.42 (m, 2H), 1.40-1.21 (m, 4H), 1.06 (s, 3H). ¹⁹F NMR (376MHz, DMSO-d₆) δ −69.09 (s), −75.06 (s), −110.63 (s). 413^(A)5-(4-Amino-2-(trifluoromethyl)imidazo[1,2-ƒ][1,2,4]triazin-7-yl)-N-((1r,4r)-4-hydroxy-4- methylcyclohexyl)-2,4-dimethylbenzenesulfonamide trifluoroacetate salt

2-CH₃, 4-CH₃ 499.1 ¹ H NMR (600 MHz, DMSO-d₆) δ 8.94 (s, 1H), 8.90 (s,1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.44 (s, 1H),3.13-3.01 (m, 1H), 2.62 (s, 3H), 2.31 (s, 3H), 1.63-1.53 (m, 2H),1.53-1.42 (m, 2H), 1.34-1.19 (m, 4H), 1.05 (s, 3H). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −69.06 (s), −74.96 (s). 414^(A)5-(4-Amino-2-(trifluoromethyl)imidazo[1,2-ƒ][1,2,4]triazin-7-yl)-2-chloro-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide

4-C1 498.0 ¹H NMR (400 MHz, CD₃OD) δ 8.99 (s, 1H), 8.25 (d, J = 8.1 Hz,1H), 8.16 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 2.17-2.05 (m, 2H),1.99-1.88 (m, 2H), 1.88-1.77 (m, 2H), 1.74- 1.63 (m, 2H) 415^(A)3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-ƒ][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide trifluoroacetate salt

— 464.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.96 (s, 1H), 8.79 (s,1H), 8.66-8.60 (m, 1H), 8.33-8.26 (m, 2H), 7.91-7.83 (m, 1H), 7.78 (t, J= 7.9 Hz, 1H), 2.03-1.94 (m, 2H), 1.91-1.82 (m, 2H), 1.75-1.67 (m, 2H),1.66-1.55 (m 2H) 416^(A) 3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-ƒ][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1] hexan-1-yl)-5-fluoro-4-methylbenzenesulfonamide trifluoroacetate salt

2-CH₃, 3-F 496.1 417^(A) 5-(4-Amino-2-(trifluoromethyl)imidazo[1,2-ƒ][1,2,4[triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-2-fluorobenzenesulfonamide trifluoroacetate salt

4-F 482.1 ¹H NMR (400 MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.97 (s, 1H), 8.95(s, 1H), 8.66 (dd, J = 7.0, 2.2 Hz, 1H), 8.33 (ddd, J = 8.5, 4.5, 2.4Hz, 1H), 8.28 (s, 1H), 7.71-7.61 (m, 1H), 2.07-1.97 (m, 2H), 1.90-1.82(m, 2H), 1.76-1.68 (m, 2H), 1.68-1.59 (m, 2H) 418^(A)5-(4-Amino-2-(trifluoromethyl)imidazo[1,2-ƒ][1,2,4]triazin-7-yl)-2-fluoro-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl) benzenesulfonamide

4-F 487.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.89 (br s, 3H), 8.61 (dd, J =6.8, 1.6 Hz, 1H), 8.37-8.27 (m, 1H), 8.25 (s, 1H), 7.63 (t, J = 9.3 Hz,1H), 4.35 (t, J = 4.9 Hz, 1H), 1.74-1.61 (m, 2H), 1.46-1.37 (m, 2H),1.37-1.26 (m, 2H), 1.12-0.94 (m 2H) 419^(A)5-(4-Amino-2-(trifluoromethyl)imidazo[1,2-ƒ][1,2,4]triazin-7-yl)-2-chloro-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl) benzenesulfonamide

4-C1 503.1 420^(B) 3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-ƒ][1,2,4]triazin-7-yl)-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-4-(methyl-d₃) benzenesulfonamidetrifluoroacetate salt

2-CD₃ 472.1 ¹H NMR (400 MHz, CD₃OD) δ 7.96 (d, J = 1.9 Hz, 1H), 7.90(dd, J = 8.1, 2.0 Hz, 1H), 7.82, (s, 1H), 7.61 (d, J = 8.1 Hz, 1H), 3.53(s, 2H), 1.75 (s, 6H)

TABLE 19

LCMS Ex. Name R⁸ R′ = [M + H]⁺ No. ¹H NMR 421^(Ex17)5-(8-amino-6-(2-fluorophenyl)imidazo[1,2-a]pyrazin-3-yl)-2-fluoro-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)benzenesulfonamide

4-F 514.3 ¹H NMR (400 MHz, DMSO-d₆) δ 8.12-8.05 (m, 2H), 8.05-7.93 (m,3H), 7.84 (s, 1H), 7.72-7.59 (m, 1H), 7.44-7.36 (m, 1H), 7.34-7.17 (m,4H), 4.15 (s, 1H), 3.26-3.15 (m, 1H), 1.67-1.55 (m, 2H), 1.55-1.42 (m,2H), 1.39-1.16 (m, 4H), 1.05 (s, 3H). 422^(Ex17)5-(8-amino-6-(3-fluoropyridin-4-yl)imidazo[1,2-a]pyrazin-3-yl)-2-fluoro-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)benzenesulfonamide

4-F 515.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (d, J = 3.2 Hz, 1H), 8.53 (d,J = 5.0 Hz, 1H), 8.25 (s, 1H), 8.15-8.07 (m, 1H), 8.06-7.92 (m, 3H),7.87 (s, 1H), 7.65 (dd, J = 9.1, 9.1 Hz, 1H), 7.39 (s, 2H), 4.15 (s,1H), 3.24-3.12 (m, 1H), 1.66-1.55 (m, 2H), 1.54-1.43 (m, 2H), 1.37-1.18(m, 4H), 1.05 (s, 3H). 423^(Ex17)5-(8-amino-6-(2-fluoro-4-(hydroxymethyl)phenyl)imidazo[1,2-a]pyrazin-3-yl)-2-fluoro-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl) benzenesulfonamide

4-F 544.4 ¹H NMR (600 MHz, DMSO-d₆) δ 8.10-8.03 (m, 2H), 8.03-7.94 (m,3H), 7.83 (s, 1H), 7.69-7.60 (m, 1H), 7.28-7.16 (m, 4H), 5.34 (br s,1H), 4.53 (s, 2H), 4.14 (s, 1H), 3.24- 3.17 (m, 1H), 1.67-1.56 (m, 2H),1.55-1.43 (m, 2H), 1.36-1.20 (m, 4H), 1.04 (s, 3H).

Example 424.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)benzenesulfonamidetrifluoroacetate salt

Step 1. (3-Methylenecyclobutane-1,1-diyl)dimethanol

To a suspension of methyltriphenylphosphonium bromide (970 mg, 2.72mmol) in THF (8 mL) at 0° C. was added potassium tert-butoxide (1.0M/THF) (2.72 mL, 2.72 mmol). The ice bath was removed and the reactionmixture was stirred at room temperature for 1 h. The resulting yellowsolution was cooled to 0° C. and a solution of diisopropyl3-oxocyclobutane-1,1-dicarboxylate (506 mg, 2.09 mmol, Synthonix) in THF(4 mL) was added dropwise via cannula. The ice bath was removed and thereaction mixture was stirred at room temperature for 1.5 h. The reactionwas quenched with saturated NH₄Cl and extracted with EtOAc. The organicextracts were washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography (0-50%EtOAc/hexanes). The product was not dried under high vacuum due tovolatility concerns.

To a solution of diisopropyl 3-methylenecyclobutane-1,1-dicarboxylate(502 mg, 2.09 mmol) in THF (6 mL) at 0° C. was added a solution oflithium aluminum hydride (2.0 M/THF, 3.13 mL, 6.27 mmol) dropwise. Thereaction mixture was warmed to room temperature and stirred for 0.5 h.The reaction mixture was diluted with ether and cooled to 0° C. Thereaction was quenched by the careful addition of 0.24 mL H₂O, followedby 0.24 mL 15% NaOH, and finally 0.72 mL H₂O. The resulting mixture waswarmed to room temperature and stirred for 15 min. Magnesium sulfate wasadded and the solids were filtered off. The filter cake was washed withether and the filtrate was concentrated to afford the product as acolorless oil (180 mg, 67%) that was used without purification.

Step 2. (1-(Iodomethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methanol(12248-19)

To a solution of (3-methylenecyclobutane-1,1-diyl)dimethanol (1.66 g,12.95 mmol) in MeCN (50 mL) was added sodium bicarbonate (1.63 g, 19.4mmol) and N-iodosuccinimide (3.50 g, 15.5 mmol) sequentially. Thereaction mixture was stirred at room temperature for 1 h. The reactionwas quenched with sat. NaS₂O₃, partitioned between water and EtOAc, andthe layers were separated. The organic layer was washed with brine,dried over MgSO₄, filtered and concentrated. The residue was purified byflash chromatography (0-100% EtOAc/hexanes) to afford the product as ayellow semi-solid (1.97 g, 60%) contaminated with succinimide. ¹H NMR(400 MHz, CDCl₃) δ 3.91 (s, 2H), 3.77 (s, 2H), 3.48 (s, 2H), 1.79-1.70(m, 2H), 1.70-1.61 (m, 2H). LCMS calculated for C₇H₁₂IO₂(M+H)⁺:m/z=255.0; found: 255.0.

Step 3. 1-Methyl-2-oxabicyclo[2.1.1]hexane-4-carboxylic acid

To a solution of (1-(iodomethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methanol(500 mg, 1.97 mmol) in methanol (6.0 mL) was added Pd—C (10 wt %, 105mg, 0.098 mmol), followed by triethylamine (0.41 mL, 2.95 mmol). Theatmosphere was replaced with hydrogen and the reaction mixture wasvigorously stirred under 1 atm of hydrogen for 5 h. The reaction mixturewas filtered through a pad of Celite®, concentrated, and the residue wasused without further purification.

A solution of (1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methanol (250 mg,1.95 mmol) in CH₂Cl₂ (3 mL)/acetonitrile (3.00 mL)/water (3.00 mL) wascooled to 0° C. and stirred rapidly while sodium periodate (1.25 g, 5.9mmol) and ruthenium(III) chloride hydrate (44.0 mg, 0.20 mmol) wereadded. The ice bath was removed and the solution was stirred at roomtemperature for 4 h. The reaction mixture was diluted with EtOAc andstirred while 1 N HCl was added until all solids dissolved. The layerswere separated and the aqueous layer was extracted with EtOAc.

The combined extracts were washed with 10% NaHSO₃ solution, brine, driedover MgSO₄, filtered, and concentrated. The residue was purified byflash chromatography (0-20% MeOH/DCM) to afford the title compound (142mg, 51%).

Step 4. Benzyl 1-methyl-2-oxabicyclo[2.1.1]hexan-4-ylcarbamate

To a solution of 1-methyl-2-oxabicyclo[2.1.1]hexane-4-carboxylic acid(142 mg, 1.0 mmol) in toluene (3.0 mL) was added triethylamine (0.28 mL,2.00 mmol), followed by diphenylphosphoryl azide (0.32 mL, 1.50 mmol).The reaction mixture was stirred at room temperature for 1 h, thenheated to reflux for 2 h. The reaction mixture was then cooled to roomtemperature and benzyl alcohol (0.208 mL, 2.0 mmol) was added. Theresulting solution was heated to reflux overnight. After cooling to roomtemperature, the reaction mixture was concentrated in vacuo and purifiedby flash chromatography (0-50% EtOAc/hexanes) to afford the product as alight yellow solid (contaminated with some benzyl alcohol). ¹H NMR (400MHz, CDCl₃) δ 7.42-7.35 (m, 5H, overlapped with benzyl alcohol), 5.12(s, 2H), 3.80 (s, 2H), 2.03-1.87 (m, 3H), 1.75 (m, 1H), 1.46 (s, 3H).LCMS calculated for C₁₄H₁₈NO₃ (M+H)⁺: m/z=248.1; found: 248.1.

Step 5. 1-Methyl-2-oxabicyclo[2.1.1]hexan-4-amine hydrochloride

To a solution of benzyl(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)carbamate (145 mg, 0.59 mmol) inMeOH (4.0 mL) was added Pd—C (10 wt %, 31.2 mg, 29 μmol). The atmospherewas replaced with hydrogen and the reaction mixture was vigorouslystirred under 1 atm of hydrogen for 1 h. The reaction mixture wasfiltered through a pad of Celite®, treated with 4 M HCl/dioxane (to formthe hydrochloride salt), concentrated, and the residue was used withoutpurification. LCMS calculated for C₆H₁₂NO (M+H)⁺: m/z=114.1; found:114.1.

Step 6. 7-o-tolylimidazo[1,2-f][1,2,4]triazin-4-amine

A mixture of 7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine (300 mg, 1.40mmol), o-tolylboronic acid (210 mg, 1.54 mmol), andDichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (57 mg, 0.07 mmol) was taken up in dioxane (8mL)/water (2 mL) and potassium carbonate (484 mg, 3.50 mmol) was added.The reaction mixture was sparged with N₂ and heated to 100° C. for 3 h.Upon cooling to room temperature, the product precipitated. Thesuspension was cooled in an ice bath and diluted with ether. The solidwas filtered, washed with ether, and air dried to yield the titlecompound as a grey solid (316 mg, 100%). LCMS calculated forC₁₂H₁₂N₅(M+H)⁺: m/z=226.1; found: 226.1.

Step 7.3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzene-1-sulfonylchloride

To a suspension of 7-(o-tolyl)imidazo[2,1-f][1,2,4]triazin-4-amine (800mg, 3.55 mmol) in DCM (10 ml) at 0° C. was added chlorosulfonic acid (8ml, 119 mmol) dropwise until complete dissolution of the startingmaterial (SM) was observed. The ice bath was removed and the resultingblack solution was allowed to warm to room temperature. After stirringfor 1 h, thionyl chloride (0.78 ml, 10.7 mmol) was added. The reactionmixture was heated to 50° C. and stirred for 0.5 h. The reaction mixturewas cooled to room temperature, diluted with DCM, and carefully added toa rapidly stirring mixture of DCM and ice chips. The precipitated solidwas filtered and the filtrate was transferred to a separatory funnel.The layers were separated and the aqueous layer was extracted with DCM.The combined organic layers were dried over anhydrous Na₂SO₄, filteredand concentrated. The resulting solid was combined with the precipitateto yield the title compound (977 mg, 85%). 1H NMR (400 MHz, DMSO) δ 9.79(s, 1H), 9.46 (s, 1H), 8.37 (s, 1H), 8.07 (s, 1H), 7.67 (s, 1H), 7.65(d, J=7.9 Hz, 1H), 7.37 (d, J=7.9 Hz, 1H), 2.22 (s, 3H). LCMS calculatedfor C₁₂H₁₁ClN₅O₂S (M+H)⁺: m/z=324.1; found: 324.0.

Step 8.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)benzenesulfonamidetrifluoroacetate salt

To a solution of 1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine hydrochloride(6.93 mg, 0.05 mmol) and DIPEA (16 μL, 0.09 mmol) in DMA (2.0 mL) at 0°C. was added a solution of3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzene-1-sulfonylchloride (10.0 mg, 0.03 mmol) in DMA (1 mL) dropwise. The 0° C. bath wasremoved, and the reaction mixture was stirred at room temp for 1 h. Thesolution was diluted with MeOH and purified by prep HPLC (pH 2). ¹H NMR(500 MHz, DMSO) δ 8.71 (s, 1H), 8.46 (s, 1H), 8.35 (s, 1H), 8.09 (s,1H), 7.96 (d, J=2.0 Hz, 1H), 7.83 (s, 1H), 7.82 (dd, J=8 Hz, 2 Hz, 1H),7.62 (d, J=8.2 Hz, 1H), 3.52 (s, 2H), 2.35 (s, 3H), 1.62 (dd, J=4.4, 1.5Hz, 2H), 1.45 (dd, J=4.4, 1.6 Hz, 2H), 1.25 (s, 3H). LCMS calculated forC₁₈H₂₁N₆O₃S (M+H)⁺: m/z=401.1; found: 401.1.

Example 425.3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methyl-N-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)benzenesulfonamidetrifluoroacetate salt

This compound was prepared according to the procedure described forExample 424, Step 8 utilizing3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylbenzene-1-sulfonylchloride (Example 472, Step 8) instead of3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzene-1-sulfonylchloride (Example 424, Step 7). ¹H NMR (500 MHz, DMSO-d₆) δ 8.75 (s,1H), 7.90 (dd, J=8.1, 2.0 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.83 (s, 1H),7.68 (d, J=8.2 Hz, 1H), 7.56 (s, 1H), 3.52 (s, 2H), 2.27 (s, 3H), 1.61(dd, J=4.4, 1.5 Hz, 2H), 1.45 (dd, J=4.3, 1.6 Hz, 2H), 1.24 (s, 3H).LCMS calculated for C₂₀H₂₁F₃N₅O₃S (M+H)⁺: m/z=468.1; found: 468.1.

Example 426.3-(4-Amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-4-trideuteromethyl-N-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)benzenesulfonamidetrifluoroacetate salt

This compound was prepared according to the procedure described forExample 424, Step 8 utilizing3-(4-amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-4-trideuteromethylbenzene-1-sulfonylchloride (Example 253, Step 3) instead of3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzene-1-sulfonylchloride (Example 424, Step 7). LCMS calculated for C₁₉H₂₀D₃N₆O₃S(M+H)⁺: m/z=418.2; found: 418.2.

Example 427.3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-(hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

Step 1. (4-(Hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-1-yl)methyl acetate

To a solution of (1-(iodomethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methanol(874 mg, 3.4 mmol, Example 424, Step 2) in DMF (6.0 mL) was added cesiumacetate (990 mg, 5.2 mmol), and the reaction mixture was heated to 100°C. for 2 h. The reaction mixture was partitioned between water and EtOAcand the layers were separated. The organic layer was washed with brine,dried over MgSO₄, filtered and concentrated. The residue was purified byflash chromatography (0-100% EtOAc/hexanes, followed by 15% MeOH/DCM) toafford the title compound (326 mg, 51%). ¹H NMR (400 MHz, CDCl₃) δ 4.34(s, 2H), 3.90 (s, 2H), 3.75 (s, 2H), 2.10 (s, 3H), 1.74 (dd, J=4.6, 1.3Hz, 2H), 1.64 (dd, J=4.6, 1.5 Hz, 2H). LCMS calculated for C₉H₁₅O₄(M+H)⁺: m/z=187.1; found: 187.0.

Step 2. 1-(Acetoxymethyl)-2-oxabicyclo[2.1.1]hexane-4-carboxylic acid

A solution of (4-(hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-1-yl)methylacetate (329 mg, 1.8 mmol) in CH₂Cl₂ (3 mL)/acetonitrile (3.00 mL)/water(3.00 mL) at 0° C. was stirred rapidly while sodium periodate (1.13 g,5.30 mmol) and ruthenium(III) chloride hydrate (40 mg, 0.18 mmol) wereadded. The ice bath was removed, and the solution was stirred at roomtemperature for 4 h. The reaction was diluted with EtOAc and stirredwhile 1M HCl was added until all solids dissolved. The layers wereseparated and the aqueous layer was extracted with EtOAc. The combinedextracts were washed with 10% NaHSO₃ solution, brine, dried over MgSO₄,filtered, and concentrated. The residue was purified by flashchromatography (0-20% MeOH/DCM) to afford the title compound as a whitesolid (340 mg, 96%). LCMS calculated for C₉H₁₃O₅(M+H)⁺: m/z=201.1;found: 201.1.

Step 3. (4-(Benzyloxycarbonylamino)-2-oxabicyclo[2.1.1]hexan-1-yl)methylacetate

To a solution of1-(acetoxymethyl)-2-oxabicyclo[2.1.1]hexane-4-carboxylic acid (350 mg,1.75 mmol) in toluene (5.0 mL) was added triethylamine (0.49 mL, 3.50mmol), followed by diphenylphosphoryl azide (0.56 mL, 2.62 mmol). Thereaction mixture was stirred at room temperature for 1 h, then heated toreflux for 2 h. The reaction mixture was then cooled to room temperatureand benzyl alcohol (0.36 mL, 3.50 mmol) was added. The resultingsolution was heated to reflux overnight. After cooling to roomtemperature, the reaction mixture was concentrated in vacuo and purifiedby flash chromatography (0-50% EtOAc/hexanes) to afford the desiredproduct as a colorless oil (391 mg, 73%). LCMS calculated for C₁₆H₂₀NO₅(M+H)⁺: m/z=306.1; found: 306.1.

Step 4. Benzyl 1-(hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-4-ylcarbamate

To a solution of(4-(((benzyloxy)carbonyl)amino)-2-oxabicyclo[2.1.1]hexan-1-yl)methylacetate (391 mg, 1.28 mmol) in MeOH (6.0 mL) was added potassiumcarbonate (230 mg, 1.67 mmol) at 0° C. The reaction mixture was warmedto room temperature and stirred for 30 min. The reaction mixture waspartitioned between water and EtOAc, and the layers were separated. Theaqueous layer was extracted with EtOAc and the combined organic layerswere washed with brine, dried over MgSO₄, filtered, and concentrated.The resulting white solid was used without purification (316 mg, 94%).LCMS calculated for C₁₄H₁₈NO₄ (M+H)⁺: m/z=264.1; found: 264.2.

Step 5. (4-Amino-2-oxabicyclo[2.1.1]hexan-1-yl)methanol

To a solution of benzyl(1-(hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)carbamate (40 mg, 0.152mmol) in MeOH (3 mL) was added palladium hydroxide on carbon (20 wt %,10.7 mg, 0.02 mmol). The atmosphere was replaced with hydrogen and thereaction mixture was vigorously stirred under 1 atm of hydrogen for 1 h.The reaction mixture was filtered through a pad of Celite®, concentratedin vacuo, and the residue was used without purification. LCMS calculatedfor C₆H₁₂NO₂ (M+H)⁺: m/z=130.1; found: 130.1.

Step 6. 3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-(hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

To a solution of (4-amino-2-oxabicyclo[2.1.1]hexan-1-yl)methanol (4.95mg, 0.038 mmol) and DIPEA (0.013 mL, 0.077 mmol) in DMA (2.0 mL) at 0°C. was added a solution of3-(4-amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzene-1-sulfonylchloride (10 mg, 0.026 mmol, 4N CF₃) in DMA (1 mL) dropwise. The 0° C.bath was removed, and the reaction mixture was stirred at room temp for1 h. The solution was diluted with MeOH and purified by prep HPLC (pH2). LCMS calculated for C₁₉H₂₀F₃N₆O₄S (M+H)⁺: m/z=485.1; found: 485.0.

Example 428.3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(1-(hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

This compound was prepared according to the procedure described forExample 427, Step 6 utilizing3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylbenzene-1-sulfonylchloride (Example 472, Step 8) instead of3-(4-amino-2-(trifluoromethyl)imidazo[1,2-J][1,2,4]triazin-7-yl)-4-methylbenzene-1-sulfonylchloride (4N CF3). LCMS calculated for C₂₀H₂₁F₃N₅O₄S (M+H)⁺: m/z=484.1;found: 484.1.

Example 429.3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(1-cyano-2-oxabicyclo[2.1.1]hexan-4-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

Step 1. tert-butyl1-(hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-4-ylcarbamate

To a solution of (4-amino-2-oxabicyclo[2.1.1]hexan-1-yl)methanol (30 mg,0.23 mmol, Example 427, Step 5) in THF (3 mL) was added sodiumbicarbonate (sat. aq.) (2 mL) followed by di-tert-butyl dicarbonate (76mg, 0.35 mmol). The reaction mixture was vigorously stirred at roomtemperature for 4 h. The reaction mixture was partitioned between waterand EtOAc, and the layers were separated. The aqueous layer wasextracted with EtOAc and the combined organic layers were washed withbrine, dried over MgSO₄, filtered, and concentrated. The residue waspurified by flash chromatography (0-100% EtOAc/hexanes) to afford theproduct as a white solid (31.5 mg, 59%). LCMS calculated for C₁₁H₁₉NO₄Na(M+Na)⁺: m/z=252.1; found: 252.1.

Step 2. tert-butyl 1-formyl-2-oxabicyclo[2.1.1]hexan-4-ylcarbamate

To a solution of tert-butyl(1-(hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)carbamate (31.5 mg,0.14 mmol) in DCM (3.0 mL) was added sodium bicarbonate (23 mg, 0.28mmol) and Dess-Martin periodinane (87 mg, 0.21 mmol). The reactionmixture was stirred at room temperature for 1 h, at which point TLCindicated complete consumption of SM. The reaction was diluted with DCM,quenched with saturated Na₂S₂O₃ and saturated NaHCO₃ (1 mL each), andvigorously stirred until two clear layers were obtained (˜10 min). Thelayers were separated and the organic layer was dried over MgSO₄,filtered, and concentrated. The residue was used without purification.

Step 3. (E)-tert-butyl1-((hydroxyimino)methyl)-2-oxabicyclo[2.1.1]hexan-4-ylcarbamate

To a solution of tert-butyl(1-formyl-2-oxabicyclo[2.1.1]hexan-4-yl)carbamate (31.5 mg, 0.14 mmol)in pyridine (3.0 mL) was added hydroxylamine hydrochloride (29 mg, 0.42mmol) and the reaction mixture was stirred at room temperature for 1 h.The reaction mixture was partitioned between water and EtOAc, and thelayers were separated. The organic layer was washed with brine, driedover MgSO₄, filtered, and concentrated. The residue was dried under highvac and used without purification. LCMS calculated for C₁₁H₁₈N₂O₄Na(M+Na)⁺: m/z=265.1; found: 265.1.

Step 4. 4-Amino-2-oxabicyclo[2.1.1]hexane-1-carbonitrile hydrochloridesalt

To a solution of tert-butyl(E)-(1-((hydroxyimino)methyl)-2-oxabicyclo[2.1.1]hexan-4-yl)carbamate(33 mg, 0.14 mmol) and triethylamine (76 μL, 0.55 mmol) in DCM (3.0 mL)(gently heated to dissolve, then cooled to 0° C.) was addedmethanesulfonyl chloride (32 μL, 0.41 mmol). The ice bath was removedand the reaction mixture was allowed to stir at room temperature for 1h. The reaction was quenched with saturated NaHCO₃ and diluted with DCM.The layers were separated and the organic layer was dried over MgSO₄,filtered, and concentrated. The residue was stirred in HCl (4 M/dioxane)(2 mL, 65.8 mmol) for 30 min and concentrated to afford the product,which was used without purification. LCMS calculated for C₆H₉N₂O (M+H)⁺:m/z=125.1; found: 125.1.

Step 5.3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(1-cyano-2-oxabicyclo[2.1.1]hexan-4-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

Prepared according to the procedure described for Example 428 utilizing4-amino-2-oxabicyclo[2.1.1]hexane-1-carbonitrile hydrochloride saltinstead of (4-amino-2-oxabicyclo[2.1.1]hexan-1-yl)methanol. LCMScalculated for C₂₀H₁₈F₃N₆O₃S (M+H)⁺: m/z=479.1; found: 479.1.

Example 430.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1s,4s)-4-(cyanomethyl)bicyclo[2.2.1]heptan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

Step 1. 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid

To a solution of dimethyl bicyclo[2.2.1]heptane-1,4-dicarboxylate (1 g,4.71 mmol, Ark Pharm, AK313189) in THF (32 mL) at 15° C. (ice waterbath) was added a solution of sodium hydroxide (188 mg, 4.71 mmol) inmethanol (2 mL). After the addition was complete, white solids began toprecipitate. The reaction mixture was stirred at room temp overnight.The reaction mixture was concentrated to dryness, slurried in hexanes,filtered, and washed with hexanes. The resulting sodium carboxylate saltwas dissolved in water, and slowly treated with 1 N aqueous hydrochloricacid until pH ˜4. The suspension was diluted with ethyl acetate andtransferred to a separatory funnel. The layers were separated and theaqueous layer was further extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over MgSO₄, andconcentrated. The resulting white solid was used without purification.¹H NMR (400 MHz, DMSO) δ 3.62 (s, 3H), 1.93 (app d, J=6.6 Hz, 4H), 1.77(s, 2H), 1.60 (q, J=9.2, 8.7 Hz, 4H).

Step 2. Methyl4-(benzyloxycarbonylamino)bicyclo[2.2.1]heptane-1-carboxylate

To a solution of 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylicacid (500 mg, 2.52 mmol) in toluene (5.0 mL) was added DIPEA (0.88 mL,5.04 mmol), followed by diphenylphosphoryl azide (0.65 mL, 3.03 mmol),and the reaction mixture was heated to 60° C. for 0.5 h, then to refluxfor 2 h. The reaction mixture was then cooled to 50° C. and benzylalcohol (0.53 mL, 5.04 mmol) was added. The resulting solution washeated to reflux for 24 h. After cooling to room temperature, thereaction mixture was diluted with EtOAc, washed with water and brine,dried over MgSO₄, filtered and concentrated. The residue was purified byflash chromatography (0-50% EtOAc/hexanes) to afford the product as acolorless oil, which was contaminated with a large amount of benzylalcohol. LCMS calculated for C₁₇H₂₂NO₄ (M+H)⁺: m/z=304.2; found: 304.1.

Step 3. Benzyl 4-(hydroxymethyl)bicyclo[2.2.1]heptan-1-ylcarbamate

To a solution of methyl4-(((benzyloxy)carbonyl)amino)bicyclo[2.2.1]heptane-1-carboxylate (500mg, 1.65 mmol) in THF (5.0 mL) was added lithium borohydride (180 mg,8.24 mmol) at room temperature and the reaction mixture was stirredovernight. The reaction mixture was cooled to 0° C., and slowly quenchedby the dropwise addition of saturated NH₄Cl. After warming to roomtemperature, the reaction mixture was partitioned between water andEtOAc, and the layers were separated. The organic layer was washed withbrine, dried over MgSO₄, filtered, and concentrated. The residue waspurified by flash chromatography (0-50-70% EtOAc/hexanes) to afford theproduct as a colorless oil (398 mg, 88%). LCMS calculated for C₁₆H₂₂NO₃(M+H)⁺: m/z=276.2; found: 276.1.

Step 4. (4-(Benzyloxycarbonylamino)bicyclo[2.2.1]heptan-1-yl)methylmethanesulfonate

To a solution of benzyl4-(hydroxymethyl)bicyclo[2.2.1]heptan-1-yl)carbamate (200 mg, 0.73 mmol)and triethylamine (0.51 mL, 3.63 mmol) in DCM (3.0 mL) at 0° C. wasadded methanesulfonyl chloride (0.11 mL, 1.45 mmol) dropwise. Afterstirring at this temperature for 15 min, the reaction mixture wasallowed to warm to room temperature and stir for 2 h. The reaction wasquenched with saturated NaHCO₃ and diluted with DCM. The layers wereseparated and the organic layer was dried over MgSO₄, filtered andconcentrated. The residue was purified by flash chromatography (0-50%EtOAc/hexanes) to afford the product as a colorless oil (252 mg, 98%).LCMS calculated for C₁₇H₂₃NO₅SNa (M+Na): m/z=376.1; found: 376.1.

Step 5. Benzyl 4-(cyanomethyl)bicyclo[2.2.1]heptan-1-ylcarbamate

To a solution of4-(((benzyloxy)carbonyl)amino)bicyclo[2.2.1]heptan-1-yl)methylmethanesulfonate (250 mg, 0.71 mmol) in DMSO (4.0 mL) was addedpotassium cyanide (461 mg, 7.07 mmol) and the reaction mixture washeated to 100° C. overnight. The reaction mixture was diluted with EtOAcand washed with water and brine. The organic layer was dried over MgSO₄,filtered, and concentrated. The residue was purified by flashchromatography (0-50% EtOAc/hexanes) to afford the product as acolorless oil (165 mg, 82%). LCMS calculated for C₁₇H₂₁N₂O₂ (M+H)⁺:m/z=285.2; found: 285.1.

Step 6. 2-(4-Aminobicyclo[2.2.1]heptan-1-yl)acetonitrile

To a solution of benzyl4-(cyanomethyl)bicyclo[2.2.1]heptan-1-yl)carbamate (165 mg, 0.58 mmol)in MeOH (4 mL) was added palladium on carbon (10 wt %, 30.9 mg, 29μmol). The vial was purged with hydrogen and the reaction mixture wasstirred under 1 atm of hydrogen for 2 h. The reaction mixture wasfiltered through a pad of Celite®, which was rinsed with additionalMeOH. The volatiles were removed in vacuo to afford the product as acolorless oil that was used without purification. LCMS calculated forC₉H₁₅N₂(M+H)⁺: m/z=151.1; found: 151.1.

Step 7.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1s,4s)-4-(cyanomethyl)bicyclo[2.2.1]heptan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

Prepared according to the procedure described for Example 424, Step 8,utilizing 2-(4-aminobicyclo[2.2.1]heptan-1-yl)acetonitrile instead of1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine hydrochloride. LCMS calculatedfor C₂₁H₂₄N₇O₂S (M+H)⁺: m/z=438.2; found: 438.1.

Example 431.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-(2-hydroxypropan-2-yl)bicyclo[2.2.1]heptan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

Step 1. 2-(4-Aminobicyclo[2.2. 1]heptan-1-yl)propan-2-ol hydrochloride

To a solution of methyl4-(((benzyloxy)carbonyl)amino)bicyclo[2.2.1]heptane-1-carboxylate (80mg, 0.26 mmol, 430, Step 2) in THF (2.0 mL) at 0° C. was addedmethyllithium (0.99 mL, 1.58 mmol) dropwise. The reaction mixture wasallowed to warm to room temperature. After stirring for 2 h, thereaction mixture was heated to 70° C. for 2 h. The reaction mixture wascooled to 0° C. and slowly quenched with 1M HCl. The aqueous layer waswashed with EtOAc and concentrated in vacuo. The product was usedwithout purification. LCMS calculated for C₁₀H₂₀NO (M+H)⁺: m/z=170.2;found: 170.2.

Step 2.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1s,4s)-4-(2-hydroxypropan-2-yl)bicyclo[2.2.1]heptan-1-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

Prepared according to the procedure described for Example 424, Step 8,utilizing 2-(4-aminobicyclo[2.2.1]heptan-1-yl)propan-2-ol hydrochloridesalt instead of 1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine hydrochloridesalt. LCMS calculated for C₂₂H₂₉N₆O₃S (M+H)⁺: m/z=457.2; found: 457.2.

Example 432.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-(1-hydroxyethyl)-2-oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt (racemic)

Step 1. 1-(4-Amino-2-oxabicyclo[2.2.2]octan-1-yl)ethanoltrifluoroacetate salt

To a solution of tert-butyl1-formyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (30 mg, 0.12 mmol,Advanced Chemblocks) in THF (1.0 mL) at 0° C. was added methylmagnesiumbromide (0.12 mL, 0.35 mmol) and the reaction mixture was allowed towarm to room temperature. The reaction mixture was quenched withsaturated NH₄Cl and partitioned between water and EtOAc. The layers wereseparated and the organic layer was washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was taken up in DCM (2.0 mL) andtreated with TFA (0.5 mL, 6.49 mmol). After stirring for 0.5 h, thevolatiles were removed in vacuo, the residue was taken up in 1:1MeCN/H₂O, and lyophilized. The residue was used without purification.LCMS calculated for C₉H₁₈NO₂ (M+H)⁺: m/z=172.1; found: 172.1.

Step 2.3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-(1-hydroxyethyl)-2-oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

Prepared according to the procedure described for Example 424, Step 8,utilizing 1-(4-amino-2-oxabicyclo[2.2.2]octan-1-yl)ethanoltrifluoroacetate salt instead of1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine hydrochloride. LCMS calculatedfor C₂₁H₂₇N₆O₄S (M+H)⁺: m/z=459.2; found: 459.2.

Example 433.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-(hydroxymethyl)-2-oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

Step 1. (4-Amino-2-oxabicyclo[2.2.2]octan-1-yl)methanol trifluoroacetatesalt

To a solution of tert-butyl1-formyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (30 mg, 0.12 mmol,Advanced Chemblocks) in EtOH (1.0 mL) at 0° C. was added sodiumborohydride (22 mg, 0.59 mmol). The reaction mixture was warmed to roomtemperature and stirred for 0.5 h. The reaction mixture was diluted withEtOAc and water, and the layers were separated. The organic layer waswashed with brine, dried over MgSO₄, filtered, and concentrated. Theresidue was dissolved in DCM (2.0 mL) and treated with TFA (0.5 mL, 6.49mmol). After stirring for 0.5 h, the volatiles were removed in vacuo,the residue was dissolved in 1:1 MeCN/H₂O, and lyophilized. The productwas used without purification. LCMS calculated for C₈H₁₆NO₂ (M+H)⁺:m/z=158.1; found: 158.2.

Step 2.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-(hydroxymethyl)-2-oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamidetrifluroacetate

Prepared according to the procedure described for Example 424, Step 8,utilizing (4-amino-2-oxabicyclo[2.2.2]octan-1-yl)methanoltrifluoroacetate salt instead of1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine hydrochloride salt. LCMScalculated for C₂₀H₂₅N₆O₄S (M+H)⁺: m/z=445.2; found: 445.2.

Example 434.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-(morpholinomethyl)-2-oxabicyclo[2.2.2]octan-4-yl)benzenesulfonamidetrifluoroacetate salt

Step 1. 1-(Morpholinomethyl)-2-oxabicyclo[2.2.2]octan-4-aminehydrochloride salt

To a solution of tert-butyl1-formyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (20 mg, 0.078 mmol,Advanced Chemblocks) in THF (1.0 mL) was added morpholine (20 μL, 0.24mmol), sodium triacetoxyborohydride (50 mg, 0.24 mmol), and 1 drop ofAcOH. The reaction mixture was stirred at room temperature overnight.The reaction mixture was quenched with saturated NaHCO₃ and extractedwith EtOAc. The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated. The residue was purified by flashchromatography (0-100% EtOAc/hexanes). The product was taken up in HCl(4 M/dioxane) (3 mL) and stirred at room temperature for 1 h. Thevolatiles were removed in vacuo and the residue was used withoutpurification. LCMS calculated for C₁₂H₂₃N₂O₂ (M+H)⁺: m/z=227.2; found:227.1.

Step 2.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-(morpholinomethyl)-2-oxabicyclo[2.2.2]octan-4-yl)benzenesulfonamide trifluoroacetate salt

Prepared according to the procedure described for Example 424, Step 8,utilizing 1-(morpholinomethyl)-2-oxabicyclo[2.2.2]octan-4-aminehydrochloride salt instead of 1-methyl-2-oxabicyclo[2.1.1]hexan-4-aminehydrochloride salt. LCMS calculated for C₂₄H₃₂N₇O₄S (M+H)⁺: m/z=514.2;found: 514.2.

Example 435.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-((3,3-difluoroazetidin-1-yl)methyl)-2-oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

Prepared according to the procedure described for Example 434, utilizing3,3-difluoroazetidine hydrochloride instead of morpholine in Step 1.LCMS calculated for C₂₃H₂₈F₂N₇O₃S (M+H)⁺: m/z=520.2; found: 520.2.

Example 436.3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-(difluoromethyl)-2-oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

Step 1. 1-(Difluoromethyl)-2-oxabicyclo[2.2.2]octan-4-aminehydrochloride

To a solution of tert-butyl1-formyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (30 mg, 0.12 mmol,Advanced Chemblocks) in DCM (1.0 mL) was added diethylaminosulfurtrifluoride (47 μL, 0.35 mmol). The reaction mixture was stirred at roomtemperature overnight and was quenched with saturated NaHCO₃. Thereaction mixture was diluted with DCM and water, and the layers wereseparated. The organic layer was dried over MgSO₄, filtered, andconcentrated.

The residue was purified by flash chromatography (0-20% EtOAc/hexanes)to afford the desired product as a white solid. This solid was taken upin HCl (4 M/dioxane) (3.0 mL) and stirred at room temperature for 1 h.The volatiles were removed in vacuo to afford the title compound (16 mg,63%). LCMS calculated for C₈H₁₄F₂NO (M+H)⁺: m/z=178.1; found: 178.1.

Step 2.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-(difluoromethyl)-2-oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

Prepared according to the procedure described for Example 424, Step 8,utilizing 1-(difluoromethyl)-2-oxabicyclo[2.2.2]octan-4-aminehydrochloride instead of 1-methyl-2-oxabicyclo[2.1.1]hexan-4-aminehydrochloride. LCMS calculated for C₂₀H₂₃F₂N₆O₃S (M+H)⁺: m/z=465.1;found: 465.1.

Example 437.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-(2,2,2-trifluoro-1-hydroxyethyl)-2-oxabicyclo[2.2.2]octan-4-yl)benzenesulfonamidetrifluoroacetate salt (racemic)

Step 1. 1-(4-Amino-2-oxabicyclo[2.2.2]octan-1-yl)-2,2,2-trifluoroethanolhydrochloride salt

A solution of tert-butyl 1-formyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate(54 mg, 0.21 mmol, Advanced Chemblocks) andtrifluoromethyltrimethylsilane (94 μL, 0.64 mmol) in DMF (2.0 mL) wascooled to 0° C. To this solution was added cesium fluoride (96 mg, 0.64mmol) and the reaction mixture was stirred overnight at roomtemperature. The reaction was quenched with saturated NaHCO₃ andpartitioned between EtOAc and water. The layers were separated and theorganic layer was washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was taken up in HCl (4 M/dioxane) (2 mL) andthe solution was stirred at room temperature for 1 h. The volatiles wereremoved in vacuo and the residue was used without purification. LCMScalculated for C₉H₁₅F₃NO₂ (M+H)⁺: m/z=226.1; found: 226.0.

Step 2.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-(2,2,2-trifluoro-1-hydroxyethyl)-2-oxabicyclo[2.2.2]octan-4-yl)benzenesulfonamidetrifluoroacetate salt

Prepared according to the procedure described for Example 424, Step 8,utilizing1-(4-amino-2-oxabicyclo[2.2.2]octan-1-yl)-2,2,2-trifluoroethanolhydrochloride instead of 1-methyl-2-oxabicyclo[2.1.1]hexan-4-aminehydrochloride. LCMS calculated for C₂₁H₂₄F₃N₆O₄S (M+H)⁺: m/z=513.2;found: 513.1.

Example 438.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-(hydroxy(phenyl)methyl)-2-oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt (racemic)

Step 1. (4-Amino-2-oxabicyclo[2.2.2]octan-1-yl)(phenyl)methanolhydrochloride salt

To a solution of tert-butyl1-formyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (25 mg, 98 mol) in THF(1.0 mL) at 0° C. was added phenylmagnesium bromide (0.33 mL, 0.98mmol). The reaction mixture was warmed to room temperature and stirredovernight. The reaction was quenched with saturated NH₄Cl and extractedwith EtOAc. The organic layer was washed with brine, dried over MgSO₄,and concentrated. The residue was dissolved in HCl (4M/dioxane) (2 mL,8.00 mmol) and stirred at room temperature for 1 h. The volatiles wereremoved in vacuo and the residue was used without purification. LCMScalculated for C₁₄H₂₀NO₂ (M+H)⁺: m/z=234.1; found: 234.2.

Step 2.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-(hydroxy(phenyl)methyl)-2-oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamidetriluoroacetate salt (racemic)

Prepared according to the procedure described for Example 424, Step 8,utilizing (4-amino-2-oxabicyclo[2.2.2]octan-1-yl)(phenyl)methanolhydrochloride instead of 1-methyl-2-oxabicyclo[2.1.1]hexan-4-aminehydrochloride. LCMS calculated for C₂₆H₂₉N₆O₄S (M+H)⁺: m/z=521.2; found:521.1.

Example 439.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-(1-methyl-1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)benzenesulfonamidetrifluoroacetate salt

Step 1. tert-butyl 1-(1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-ylcarbamate

To a solution of tert-butyl1-formyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (50 mg, 0.20 mmol,Advanced Chemblocks) in ammonia (7 N/MeOH) (1 mL, 7.0 mmol) was addedglyoxal (67 μL, 0.59 mmol) and the reaction mixture was stirred at roomtemperature overnight. The volatiles were removed in vacuo and theresidue was partitioned between EtOAc and water. The layers wereseparated and the organic layer was washed with brine, dried over MgSO₄,filtered and concentrated. The residue was purified by flashchromatography (0-15% MeOH/DCM) to afford the title compound (24 mg,42%). LCMS calculated for C₁₅H₂₄N₃O₃ (M+H)⁺: m/z=294.2; found: 294.2.

Step 2. 1-(1-Methyl-1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-aminehydrochloride salt

To a solution of tert-butyl1-(1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (24 mg, 0.08mmol) in acetonitrile (3.0 mL) was added potassium carbonate (34 mg,0.25 mmol), followed by methyl iodide (15 μL, 0.25 mmol), and thereaction mixture was heated to 60° C. overnight. The reaction mixturewas cooled to room temperature and partitioned between water and EtOAc.The layers were separated and the organic layer was washed with brine,dried over MgSO₄, filtered and concentrated. The residue was taken up inHCl (4M/dioxane, 3.0 mL) and stirred at room temperature for 1 h. Thevolatiles were removed in vacuo and the product was used withoutpurification. LCMS calculated for C₁₁H₁₈N₃O (M+H)⁺: m/z=208.1; found:208.1.

Step 3.3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-(1-methyl-1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)benzenesulfonamidetrifluoroacetate salt

Prepared according to the procedure described for Example 424, Step 8,utilizing 1-(1-methyl-1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-aminehydrochloride instead of 1-methyl-2-oxabicyclo[2.1.1]hexan-4-aminehydrochloride. LCMS calculated for C₂₃H₂₇N₈O₃S (M+H)⁺: m/z=495.2; found:495.3.

Example 440.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-(oxazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)benzenesulfonamidetrifluoroacetate salt

Step 1. 1-(Oxazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-amine hydrochloridesalt

To a solution of tert-butyl1-formyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (30 mg, 0.12 mmol,Advanced Chemblocks) in methanol (1.0 mL) was added potassium carbonate(49 mg, 0.35 mmol), followed by TosMIC (34 mg, 0.18 mmol), and thereaction mixture was heated to reflux overnight. The reaction mixturewas partitioned between water and EtOAc, and the layers were separated.The organic layer was washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by flash chromatography (0-70%EtOAc/hexanes) to afford the desired product as a white solid. This wastaken up in HCl (4M/dioxane, 2.0 mL) and stirred at room temperature for1 h. The volatiles were removed in vacuo to afford the title compound(18 mg, 66%). LCMS calculated for C₁₀H₁₅N₂O₂ (M+H)⁺: m/z=195.1; found:195.1.

Step 2.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-(oxazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)benzenesulfonamide trifluoroacetate salt

Prepared according to the procedure described for Example 424, Step 8,utilizing 1-(oxazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-amine hydrochloridesalt instead of 1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine hydrochloridesalt. LCMS calculated for C₂₂H₂₄N₇O₄S (M+H)⁺: m/z=482.2; found: 482.1.

Example 441.3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(1-(2-hydroxypropan-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

Step 1. tert-butyl 1-acetyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate

To a solution of tert-butyl1-(1-hydroxyethyl)-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (213 mg, 0.79mmol, 432, Step 1) in DCM (5 mL) at 0° C. was added sodium bicarbonate(198 mg, 2.36 mmol), followed by Dess-Martin periodinane (499 mg, 1.18mmol), and the reaction mixture was allowed to warm to room temperature.After stirring for 1 h, TLC indicated complete consumption of SM. Thereaction mixture was diluted with DCM, quenched with saturated Na₂S₂O₃and saturated NaHCO₃. The suspension was vigorously stirred until twoclear layers were obtained. The layers were separated and the organiclayer was dried over MgSO₄, filtered and concentrated. The residue waspurified by flash chromatography (0-40% EtOAc/hexanes) to afford theproduct as a white solid (104 mg, 49%).

Step 2. 2-(4-Amino-2-oxabicyclo[2.2.2]octan-1-yl)propan-2-olhydrochloride salt

To a solution of tert-butyl1-acetyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (30 mg, 0.11 mmol) inTHF (2.0 mL) at 0° C. was added methylmagnesium bromide (0.19 mL, 0.56mmol). The reaction mixture was allowed to warm to room temperature andstir for 1 h. The reaction was quenched with water and extracted withEtOAc. The organic extracts were washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was taken up in HCl (4M/dioxane,3 mL) and stirred at room temperature for 1 h. The volatiles wereremoved in vacuo and the residue was used without purification. LCMScalculated for C₁₀H₂₀NO₂ (M+H)⁺: m/z=186.1; found: 186.2.

Step 3.3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(1-(2-hydroxypropan-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

Prepared according to the procedure described for Example 428, utilizing2-(4-amino-2-oxabicyclo[2.2.2]octan-1-yl)propan-2-ol hydrochloride saltinstead of (4-amino-2-oxabicyclo[2.1.1]hexan-1-yl)methanol. LCMScalculated for C₂₄H₂₉F₃N₅O₄S (M+H)⁺: m/z=540.2; found: 540.1.

Example 442.3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1s,4s)-4-hydroxybicyclo[2.2.1]heptan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

Step 1. 4-Hydroxybicyclo[2.2.1]heptane-1-carboxylic acid

To a solution of methyl 4-hydroxybicyclo[2.2.1]heptane-1-carboxylate(487 mg, 2.86 mmol, Advanced Chemblocks, L13452) in MeOH (5 mL) wasadded sodium hydroxide (572 mg, 14.3 mmol) in water (5.0 mL) and thereaction mixture was stirred at room temperature. After 1 h, thereaction mixture was acidified with 1 M HCl to pH 1 and extracted withthree portions of EtOAc. The organic extracts were washed with brine,dried over MgSO₄, filtered and concentrated to afford a tan solid (257mg, 58%) that was used without purification.

Step 2. 4-aminobicyclo[2.2.1]heptan-1-ol hydrochloride salt

To a solution of 4-hydroxybicyclo[2.2.1]heptane-1-carboxylic acid (257mg, 1.65 mmol) and triethylamine (0.28 mL, 1.98 mmol) in toluene (6.0mL) was added diphenylphosphoryl azide (0.43 mL, 1.98 mmol) and thereaction mixture was heated to reflux for 2 h. The reaction mixture wasdiluted with EtOAc, washed with water and brine, dried over MgSO₄ andconcentrated. The residue was taken up in a 1:1 mixture of AcOH and 15%HCl (1 mL each) and stirred at room temperature for 1 h. The reactionmixture was washed with EtOAc and the aqueous layer was concentrated todryness to afford the title compound, which was used withoutpurification.

Step 3.3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1s,4s)-4-hydroxybicyclo[2.2.1]heptan-1-yl)-4-methylbenzenesulfonamide trifluoroacetate salt

Prepared according to the procedure described for Example 424, Step 8,utilizing 4-aminobicyclo[2.2.1]heptan-1-ol hydrochloride salt instead of1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine hydrochloride salt. LCMScalculated for C₁₉H₂₃N₆O₃S (M+H)⁺: m/z=415.1; found: 415.2.

Example 443.3-(4-Amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-hydroxybicyclo[2.2.1]heptan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

Prepared according to the procedure described for Example 442, utilizing3-(4-amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzene-1-sulfonylchloride (4N Me SO₂Cl) instead of3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzene-1-sulfonylchloride in Step 3. LCMS calculated for C₂₀H₂₅N₆O₃S (M+H)⁺: m/z=429.2;found: 429.1.

Example 444.3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(4-hydroxybicyclo[2.2.1]heptan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate salt

Prepared according to the procedure described for Example 442, utilizing3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylbenzene-1-sulfonylchloride (Example 472, Step 8) instead of3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzene-1-sulfonylchloride (Example 424, Step 7) in Step 3. LCMS calculated forC₂₁H₂₃F₃N₅O₃S (M+H)⁺: m/z=482.1; found: 482.1.

Example 445.8-Amino-3-(5-(N-((3,3-difluorocyclobutyl)methyl)sulfamoyl)-2-methylphenyl)-N-methylimidazo[1,2-a]pyrazine-6-carboxamidetrifluoroacetate salt

Step 1.N-(3,3-difluorocyclobutyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

To a solution of 3-bromo-4-methylbenzenesulfonyl chloride (300 mg, 1.11mmol) and i-Pr₂NEt (0.58 mL, 3.33 mmol in DCM (11 mL) at 0° C. was addedDMAP (6.80 mg, 56 μmol) and (3,3-difluorocyclobutyl)methanaminehydrochloride (193 mg, 1.22 mmol) in one portion. After stirring at 0°C. for 2 h, the reaction was quenched by adding saturated NaHCO₃. Thelayers were separated and the organic layer was dried over MgSO₄,filtered, and concentrated. The residue was used without purification.

A mixture of3-bromo-N-((3,3-difluorocyclobutyl)methyl)-4-methylbenzenesulfonamide(338 mg, 0.95 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (254 mg, 1.0mmol), potassium acetate (309 mg, 3.15 mmol), andDichlorobis(triphenylphosphine)-palladium(II) (27 mg, 38 μmol) in THF(2.7 mL) was degassed with N₂ for 5 min. The mixture was heated in amicrowave at 140° C. for 20 minutes. The reaction mixture was dilutedwith EtOAc and filtered through Celite®, rinsing with EtOAc. Thefiltrate was washed with water and then brine, dried over Na₂SO₄,filtered, and concentrated. Purification via silica gel chromatography(10-50% EtOAc/DCM) afforded the desired product as a yellow oil. LCMScalculated for C₁₈H₂₇BF₂NO₄S (M+H)⁺: m/z=402.2; found: 402.1.

Step 2.3-(8-Amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-N-((3,3-difluorocyclobutyl)methyl)-4-methylbenzenesulfonamide

A mixture of 6-bromo-3-iodoimidazo[1,2-a]pyrazin-8-amine (120 mg, 0.35mmol, 3N Br I),N-((3,3-difluorocyclobutyl)methyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide(156 mg, 0.389 mmol), and tetrakis(triphenylphosphine)palladium(0)(24.96 mg, 0.022 mmol) in ethanol (4 mL)/2.0 M sodium carbonate in water(0.35 mL) was degassed for 5 min with N₂. The reaction mixture was thenheated in a microwave reactor at 130° C. for 20 min. The reactionmixture was diluted with MeOH and filtered through a plug of Celite®.The filtrate was concentrated and the residue was purified by flashchromatography (0-100% EtOAc/hexanes) to afford the title compound (170mg, 99%). LCMS calculated for C₁₈H₁₉BrF₂N₅O₂S (M+H)⁺: m/z=486.0; found:486.0.

Step 3. Methyl8-amino-3-(5-(N-((3,3-difluorocyclobutyl)methyl)sulfamoyl)-2-methylphenyl)imidazo[1,2-a]pyrazine-6-carboxylate

In a 40 mL vial, a solution of3-(8-amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-N-((3,3-difluorocyclobutyl)methyl)-4-methylbenzenesulfonamide(200 mg, 0.41 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (34 mg, 41 μmol), and triethylamine (0.23 mL,1.65 mmol) in methanol (10 mL) was saturated with CO by bubbling the gasthrough the solution for 5 min. The vessel was heated to 60° C. under 1atm of CO for 5 h. Upon standing at room temperature overnight, theproduct precipitated. The suspension was treated with ether and cooledin an ice bath. The solid was filtered, washed with ether, and air driedto yield the desired product as a tan solid (84 mg, 44%). LCMScalculated for C₂₀H₂₂F₂N₅O₄S (M+H)⁺: m/z=466.1; found: 466.2.

Step 4.8-Amino-3-(5-(N-((3,3-difluorocyclobutyl)methyl)sulfamoyl)-2-methylphenyl)-N-methylimidazo[1,2-a]pyrazine-6-carboxamidetrifluoroacetate salt

To a solution of methyl8-amino-3-(5-(N-((3,3-difluorocyclobutyl)methyl)sulfamoyl)-2-methylphenyl)imidazo[1,2-a]pyrazine-6-carboxylate(15 mg, 0.032 mmol) in THF (2.0 mL) at rt was added methanamine (0.161mL, 0.322 mmol), and trimethylaluminum (0.081 mL, 0.161 mmol) (2M intoluene). The resultant solution was heated at 80° C. for 3 h. Aftercooling to rt, MeOH (2 mL) was added. The mixture was stirred at rt for1 h and filtered through Celite®. The filtrate was concentrated undervacuum. The residue was dissolved in MeOH (5 mL) and purified by pH 2prep-LCMS to afford the desired product. LCMS calculated forC₂₀H₂₃F₂N₆O₃S (M+H)⁺: m/z=465.1; found: 465.1.

Example 446 listed in following table was prepared analogously toExample 445 utilizing the appropriate commercially available amine:

Ex. No. Name R LCMS 446 8-amino-N-cyclobutyl-3-(5-(N-((3,3-difluorocyclobutyl)methyl)sulfamoyl)- 2-methylphenyl)imidazo[1,2-a]pyrazine-6-carboxamide trifluoroacetate salt

505.2

Example 447.8-Amino-3-(5-(N-(3,3-difluorocyclobutyl)sulfamoyl)-2-methylphenyl)-N-methylimidazo[1,2-a]pyrazine-6-carboxamidetrifluoroacetate salt

Prepared according to the procedure described for Example 445 utilizing3,3-difluorocyclobutanamine hydrochloride salt instead of(3,3-difluorocyclobutyl)methanamine hydrochloride salt in Step 1. LCMScalculated for C₁₉H₂₁F₂N₆O₃S (M+H)⁺: m/z=451.1; found: 451.1.

Example 448 in the following table was prepared analogously to Example447 utilizing the appropriate commercially available amine:

Ex. No. Name R LCMS 448 8-amino-N-cyclobutyl-3-(5-(N-(3,3-difluorocyclobutyl)sulfamoyl)-2- methylphenyl)imidazo[1,2-a]pyrazine-6-carboxamide trifluoroacetate salt

491.1

Example 449.8-Amino-3-(5-(N-((3S,6R)-6-(cyanomethyl)tetrahydro-2H-pyran-3-yl)sulfamoyl)-2-methylphenyl)-N-methylimidazo[1,2-a]pyrazine-6-carboxamidetrifluoroacetate salt

Prepared according to the procedure described for Example 445 utilizing2-((2R,5S)-5-aminotetrahydro-2H-pyran-2-yl)acetonitrile instead of(3,3-difluorocyclobutyl)methanamine hydrochloride in Step 1. LCMScalculated for C₂₂H₂₆N₇O₄S (M+H)⁺: m/z=484.2; found: 484.1.

Examples 450 and 451 in the following table were prepared analogously toExample 449 utilizing the appropriate commercially available amine:

Ex. No. Name R LCMS 450 8-amino-3-(5-(N-((3S,6R)-6-(cyanomethyl)tetrahydro-2H-pyran- 3-yl)sulfamoyl)-2-methylphenyl)-N-cyclobutylimidazo[1,2-a]pyrazine-6- carboxamide trifluoroacetate salt

524.2 451 8-amino-3-(5-(N-((3S,6R)-6- (cyanomethyl)tetrahydro-2H-pyran-3-yl)sulfamoyl)-2-methylphenyl)-N- (3,3-difluorocyclobutyl)imidazo[1,2-a]pyrazine-6-carboxamide trifluoroacetate salt

560.2

Example 452.8-Amino-N-(4-(diethylamino)butyl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamidetrifluoroacetate salt

To a solution of methyl8-amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazine-6-carboxylate(15 mg, 42 μmol, Example 458, Step 1) in THF (1.0 mL) at roomtemperature was added N¹,N¹-diethylbutane-1,4-diamine (80 mg, 0.41mmol), and trimethylaluminum (0.10 mL, 0.21 mmol) (2 M in toluene). Theresultant solution was heated at 80° C. for 3 h. After cooling to roomtemperature, MeOH (2 mL) was added. The mixture was stirred at roomtemperature for 1 h and filtered through Celite. R The filtrate wasconcentrated under vacuum. The residue was dissolved in MeOH (5 mL) andpurified by pH 2 prep-LCMS to afford the desired product. LCMScalculated for C₂₃H₃₃N₆O₃S (M+H)⁺: m/z=473.2; found: 473.2.

The compounds listed in the following table were prepared analogously toExample 452 utilizing the appropriate commercially available amine:

Ex. No. Name R LCMS 453 8-amino-N-(2-(1-methyl-1H-pyrazol-4-yl)ethyl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide trifluoroacetate salt

454.1 454 8-amino-N-(5-(furan-2-yl)-1H-pyrazol-3-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide trifluoroacetate salt

478.0 455 8-amino-3-(2-methyl-5-(methylsulfonyl)phenyl)-N-(5-(4-methylpiperadzin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyrazine-6- carboxamide trifluoroacetate salt

521.3 456 8-amino-3-(2-methyl-5-(methylsulfonyl)phenyl)-N-((4-(trifluoromethyl)cyclohexyl)methyl)imidazo[1,2-a]pyrazine-6-carboxamide trifluoroacetate salt (1:1cis/trans isomers)

510.1 457 N-(3-(1H-pyrazol-1-yl)propyl)-8-amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo [1,2-a]pyrazine-6-carboxamidetrifluoroacetate salt

454.1

Example 458.8-Amino-N-(1-(2-methoxyethyl)piperidin-3-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamidetrifluoroacetate salt

Step 1. methyl8-amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazine-6-carboxylate

In a 40 mL vial, a solution of6-bromo-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-amine(400 mg, 1.05 mmol),Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (86 mg, 0.11 mmol), and triethylamine (0.59 mL,4.20 mmol) in methanol (8 mL) was saturated with CO by bubbling the gasthrough the solution for 5 min. The vessel was heated to 60° C. under 1atm of CO for 5 h. The volatiles were removed in vacuo and the resultingsolid was suspended in EtOAc, filtered, washed with additional EtOAc,and air dried to yield the desired product as a light brown solid. LCMScalculated for C₁₆H₁₇N₄O₄S (M+H)⁺: m/z=361.1; found: 361.1.

Step 2.8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)-N-(piperidin-3-yl)imidazo[1,2-a]pyrazine-6-carboxamidetrifluoroacetate salt

To a solution of methyl8-amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazine-6-carboxylate(100 mg, 0.28 mmol) in THF (3.0 mL) at room temperature was addedtert-butyl 3-aminopiperidine-1-carboxylate (0.19 mL, 0.83 mmol), andtrimethylaluminum (2M/toluene, 0.42 mL, 0.83 mmol). The resultantsolution was heated at 80° C. for 3 h. After cooling to roomtemperature, MeOH (2 mL) was added. The mixture was stirred at roomtemperature for 1 h and filtered through Celite®. The filtrate wasconcentrated under vacuum. The residue was dissolved in DCM (3 mL) andtrifluoroacetic acid (2 mL) was added. After stirring for 0.5 h, thevolatiles were removed in vacuo and the residue was used withoutpurification. LCMS calculated for C₂₀H₂₅N₆O₃S (M+H)⁺: m/z=429.2; found:429.1.

Step 3.8-amino-N-(1-(2-methoxyethyl)piperidin-3-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamidetrifluoroacetate salt

To a solution of8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)-N-(piperidin-3-yl)imidazo[1,2-a]pyrazine-6-carboxamidetrifluoroacetate salt (15 mg, 28 μmol) in acetonitrile (1.0 mL) wasadded potassium carbonate (12 mg, 83 μmol), followed by 2-bromoethylmethyl ether (6 μl, 83 μmol), and the reaction mixture was heated to 60°C. overnight. No conversion was observed so the temperature wasincreased to 90° C. for a further 24 h. There was still no conversion soseveral equivalents of cesium carbonate and excess electrophile wereadded. Heating was continued at 90° C. overnight. Full conversion wasobserved by LCMS. The reaction mixture was partitioned between water andEtOAc, and the layers were separated. The organic layer was washed withbrine, dried over MgSO₄, filtered and concentrated. The residue waspurified by prep HPLC (pH 2). LCMS calculated for C₂₃H₃₁N₆O₄S (M+H)⁺:m/z=487.2; found: 487.2.

Example 459.8-Amino-N-(1-(cyanomethyl)piperidin-3-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamidetrifluoroacetate salt

Prepared according to the procedure described for Example 458, utilizingbromoacetonitrile instead of 2-bromoethyl methyl ether. LCMS calculatedfor C₂₂H₂₆N₇O₃S (M+H)⁺: m/z=468.2; found: 468.1.

Example 460.8-Amino-N-(1-(2-hydroxyethyl)piperidin-3-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamidetrifluoroacetate salt (racemic)

Prepared according to the procedure described for Example 458, utilizing2-bromoethanol instead of 2-bromoethyl methyl ether. LCMS calculated forC₂₂H₂₉N₆O₄S (M+H)⁺: m/z=473.2; found: 473.1.

Example 461. Methyl3-(8-amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamido)piperidine-1-carboxylatetrifluoroacetate salt

To a solution of8-amino-3-(2-methyl-5-(methylsulfonyl)phenyl)-N-(piperidin-3-yl)imidazo[1,2-a]pyrazine-6-carboxamidetrifluoroacetate salt (12 mg, 22 μmol, Example 458, Step 1) and DIPEA(19 μL, 0.11 mmol) in acetonitrile (1.0 mL) was added methylchloroformate (9 μL, 0.11 mmol) at 0° C., and the reaction mixture wasallowed to warm to room temperature. After stirring for 1 h, thereaction mixture was diluted with MeOH and purified by prep HPLC (pH 2).LCMS calculated for C₂₂H₂₇N₆O₅S (M+H)+: m/z=487.2; found: 487.2.

Example 462.8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)-N-(1-(methylsulfonyl)piperidin-3-yl)imidazo[1,2-a]pyrazine-6-carboxamidetrifluoroacetate salt

Prepared according to the procedure described for Example 461, utilizingmethanesulfonyl chloride instead of methyl chloroformate. LCMScalculated for C₂₁H₂₇N₆O₅S₂ (M+H)⁺: m/z=507.1; found: 507.1.

Example 463.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-4-methylbenzenesulfonamide

Step 1.N-((1r,4r)-4-Hydroxy-4-methylcyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 1, steps 1 and 2 substituting(1r,4r)-4-amino-1-methylcyclohexan-1-ol for trans-4-aminocyclohexanol instep 1. LCMS for C₂₀H₃₂BNO₅S (M+H)⁺: calculated m/z=410.2; found 410.1.

Step 2.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-4-methylbenzenesulfonamide

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 39, substitutingN-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamideforN-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide.¹H NMR (600 MHz, d₆-DMSO) δ 8.33 (br s, 1H), 8.25 (br s, 1H), 8.07 (s,1H), 7.93 (d,J=1.9 Hz, 1H), 7.83-7.76 (m, 2H), 7.59 (t, J=8.0 Hz, 2H),4.12 (s, 1H),3.10 (s, 1H), 2.34 (s, 3H), 1.60(m, 2H), 1.49(m, 2H), 1.27(m, 4H), 1.05 (s, 3H) LCMS for C₁₉H₂₄N₆I₃S (M+H)⁺: calculated m/z=417.2;found 417.1.

Example 464.(R)-3-(5-((3-Aminopiperidin-1-yl)sulfonyl)-2-methylphenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine tris(2,2,2-trifluoroacetate)

Step 1. tert-Butyl(R)-(1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidin-3-yl)carbamate

The desired compound was prepared according to the procedure of Example466, step 2, using3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylbenzenesulfonylchloride and tert-butyl (R)-piperidin-3-ylcarbamate [Combi-Blocks,AM-1743] as the starting materials. LCMS for C₂₄H₃₀F₃N₆O₄S (M+H)⁺:m/z=555.2; Found: 555.3.

Step 2.(R)-3-(5-((3-Aminopiperidin-1-yl)sulfonyl)-2-methylphenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-aminetris(2,2,2-trifluoroacetate)

A solution of tert-butyl(R)-(1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidin-3-yl)carbamate(0.019 g, 0.034 mmol) in dichloromethane (0.86 mL) was treated with TFA(0.86 mL) and stirred for 1 h. The reaction mixture was concentrated toa residue. Purification by preparative LCMS (XBridge C18 Column, elutingwith a gradient of acetonitrile in water with 0.1% trifluoroacetic acid,at flow rate of 60 mL/min) gave the desired product (22 mg, 79%). ¹H NMR(400 MHz, DMSO-d₆) δ 8.08-7.89 (m, 4H), 7.83 (s, 1H), 7.82-7.59 (m, 6H),3.37 (d, J=11.2 Hz, 1H), 3.34-3.23 (m, 1H), 3.19-3.01 (m, 1H), 2.98-2.72(m, 2H), 2.30 (s, 3H), 1.87-1.70 (m, 2H), 1.65-1.49 (m, 1H), 1.49-1.31(m, 1H). LCMS for C₁₉H₂₂F₃N₆O₂S (M+H)⁺: m/z=455.1; Found: 455.1.

Example 465.5-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-((3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)-2,4-dimethylbenzenesulfonamide

Step 1. Methyl(2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylate

A solution of(2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylicacid (0.199 g, 0.811 mmol) [Advanced ChemBlocks, I-9006] in methanol(1.62 mL) at 0° C. was treated with (trimethylsilyl)diazomethanesolution in diethyl ether (0.811 mL, 1.62 mmol) and stirred for 2 h. Thereaction mixture was concentrated to give the desired product (210 mg,100%) as a white solid that was used without further purification. LCMSfor C₁₂H₂₁NO₅Na (M+Na)⁺: m/z=282.1; Found: 282.0.

Step 2. tert-Butyl((3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)carbamate

A solution of methyl(2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylate(0.250 g, 0.964 mmol) in tetrahydrofuran (7.42 mL) at 0° C. was treatedwith methylmagnesium bromide (3.0 M in ether) (1.61 mL, 4.82 mmol)dropwise, and stirred at room temperature for 2 h. The reaction mixturewas cooled to 0° C., quenched with saturated ammonium chloride solution(20 mL), and extracted with ethyl acetate. The organic layer wasseparated, dried over sodium sulfate, filtered, and concentrated to givea crude residue. Purification by flash column chromatography using ethylacetate in hexanes (0%-60%) gave the desired product (133 mg, 53.2%) asa white solid. LCMS for C₁₃H₂₅NO₄Na (M+Na)⁺: m/z=282.2; Found: 282.2.

Step 3. 2-((2S,5R)-5-Aminotetrahydro-2H-pyran-2-yl)propan-2-olhydrochloride

A solution of tert-butyl((3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)carbamate(0.133 g, 0.513 mmol) in dioxane (1.03 mL) was treated with 4 M HCl indioxane (3.85 mL, 15.4 mmol) and stirred for 3 h. The reaction mixturewas concentrated and reconcentrated from acetonitrile (2×) to give thedesired product (103 mg, quantitative) as a white solid that was usedwithout further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (s, 3H),4.24 (br s, 1H), 4.01 (d, J=8.0 Hz, 1H), 3.22 (t, J=10.7 Hz, 1H),3.08-2.97 (m, 1H), 2.93 (d, J=10.8 Hz, 1H), 2.13-1.99 (m, 1H), 1.87-1.69(m, 1H), 1.55-1.41 (m, 1H), 1.41-1.24 (m, 1H), 1.06 (s, 3H), 1.00 (s,3H).

Step 4.5-Bromo-N-((3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)-2,4-dimethylbenzenesulfonamide

The desired compound was prepared according to the procedure of example1, step 1, using 5-bromo-2,4-dimethylbenzenesulfonyl chloride and2-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)propan-2-ol hydrochloride asthe starting materials. LCMS for C₁₆H₂₄BrNO₄SNa (M+Na)⁺: m/z=428.1,430.0; Found: 428.0, 430.0.

Step 5.N-((3R,6S)-6-(2-Hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

The desired compound was prepared according to the procedure of example1, step 2, using5-bromo-N-((3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)-2,4-dimethylbenzenesulfonamideas the starting material. LCMS for C₂₂H₃₆BNO₆SNa (M+Na)⁺: m/z=476.2;Found: 476.2.

Step 6.5-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-((3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)-2,4-dimethylbenzenesulfonamide

The desired compound was prepared according to the procedure of example1, step 3, using 3-iodo-6-methylimidazo[1,2-a]pyrazin-8-amine andN-((3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamideas the starting materials. ¹H NMR (400 MHz, DMSO-d₆) δ 7.83 (d, J=7.2Hz, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 7.48 (s, 1H), 7.00 (s, 1H), 6.95(s, 2H), 4.15 (s, 1H), 3.76-3.60 (m, 1H), 3.02-2.89 (m, 1H), 2.84 (d,J=10.4 Hz, 1H), 2.61 (s, 3H), 2.18 (s, 3H), 2.13 (s, 3H), 1.81-1.55 (m,2H), 1.45-1.27 (m, 1H), 1.27-1.09 (m, 2H), 1.00 (s, 3H), 0.93 (s, 3H).LCMS for C₂₃H₃₂N₅O₄S (M+H)⁺: m/z=474.2; Found: 474.2.

Example 466.3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-((3S,6R)-6-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-5-fluoro-4-methylbenzenesulfonamide

Step 1. 3-Bromo-5-fluoro-4-methylbenzenesulfonyl chloride

A round-bottom flask was charged with water (80 mL) and placed in an icebath. To this was added thionyl chloride (13.2 mL, 180 mmol) over 35 minusing an addition funnel. The reaction mixture was warmed to roomtemperature with the aid of a room temperature water bath, treated withcopper(I) chloride (0.194 g, 1.96 mmol), and placed in a brine-ice bath.Concurrently in a separate round-bottom flask,3-bromo-5-fluoro-4-methylaniline (8.00 g, 39.2 mmol) [Oxchem, AX8258142]was added dropwise to concentrated hydrochloric acid (98 mL) (theaniline was melted using a 50° C. oil bath before addition) which gave afree-flowing but thick slurry. The reaction mixture was placed in abrine-ice bath and the slurry became thicker but stirring was maintainedwith a very large stir bar. The reaction mixture was treated with asolution of sodium nitrite (2.98 g, 43.1 mmol) in water (5.58 mL) over 5mins at −3 to 0° C. which led to dissolution of most of the solids and amuch thinner orange slurry. After stirring for 5 mins, the reactionmixture was added to the chilled thionyl chloride solution dropwise inportions by pipette over 15 mins with gas evolution observed andtemperature ranging between −7 to −6° C. The reaction mixture wasstirred for 2.5 h, warmed to room temperature and stirred for 1 hr. Thereaction mixture was diluted with water (250 mL) and extracted withethyl acetate (3×200 mL). The combined organic extracts were washed withbrine (100 mL), dried with magnesium sulfate, filtered, and concentratedto give the desired product (9.79 g, 87%) as an amber oil that was usedwithout further purification.

Step 2.3-bromo-N-((3S,6R)-6-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-5-fluoro-4-methylbenzenesulfonamide

A solution of 2-((2R,5S)-5-aminotetrahydro-2H-pyran-2-yl)acetonitrilehydrochloride/2-((2S,5 S)-5-aminotetrahydro-2H-pyran-2-yl)acetonitrilehydrochloride (0.184 g, 1.04 mmol) [WO 2015/168246] in dichloromethane(6.96 mL) at 0° C. was treated with triethylamine (0.436 mL, 3.13 mmol)and DMAP (2.55 mg, 0.021 mmol) followed by3-bromo-5-fluoro-4-methylbenzenesulfonyl chloride (0.30 g, 1.04 mmol) asa solution in dichloromethane (1.00 mL) in one portion at 0° C. andstirred at room temperature for 1 h. The reaction mixture was pouredinto saturated sodium bicarbonate solution (20 mL) and extracted withdichloromethane (2×20 mL). The combined organic extracts were washedwith brine, dried with sodium sulfate, filtered, and concentrated to aresidue. Purification by flash column chromatography using ethyl acetate(contained 5% MeOH) in hexanes (0%-60%) gave the desired trans product(185 mg, 45.3%) as a white solid. ¹H NMR (600 MHz, CDCl₃) δ 7.84 (s,1H), 7.48 (dd, J=8.2, 1.5 Hz, 1H), 4.54 (d, J=8.0 Hz, 1H), 3.96 (ddd,J=11.1, 4.7, 2.2 Hz, 1H), 3.62-3.38 (m, 1H), 3.37-3.20 (m, 1H), 3.08(dd, J=10.9, 10.9 Hz, 1H), 2.49 (d, J=5.9 Hz, 2H), 2.39 (d, J=2.3 Hz,3H), 2.11-1.92 (m, 1H), 1.89-1.76 (m, 1H), 1.53-1.43 (m, 1H), 1.42-1.32(m, 1H). LCMS for C₁₄H₁₆ BrFN₂O₃SNa (M+Na): m/z=413.0, 415.0; Found:413.0, 415.0.

Step 3.N-((3S,6R)-6-(Cyanomethyl)tetrahydro-2H-pyran-3-yl)-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

The desired compound was prepared according to the procedure of example1, step 2, using3-bromo-N-((3S,6R)-6-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-5-fluoro-4-methylbenzenesulfonamideas the starting material. LCMS for C₂₀H₂₈BFN₂O₅SNa (M+Na)⁺: m/z=461.2;Found: 461.2.

Step 4.3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-((3S,6R)-6-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-5-fluoro-4-methylbenzenesulfonamide

The desired compound was prepared according to the procedure of example1, step 3, using7-bromo-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine andN-((3S,6R)-6-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamideas the starting materials. ¹H NMR (400 MHz, DMSO-d₆) δ 9.11-8.76 (m,2H), 8.04-7.87 (m, 2H), 7.82 (s, 1H), 7.71 (d, J=8.9 Hz, 1H), 3.81-3.66(m, 1H), 3.50-3.36 (m, 1H), 3.17-2.90 (m, 2H), 2.70 (dd, J=16.9, 4.0 Hz,1H), 2.57 (dd, J=16.9, 6.6 Hz, 1H), 2.23 (s, 3H), 1.83-1.54 (m, 2H),1.51-1.16 (m, 2H). LCMS for C₂₀H₂₀F₄N₇O₃S (M+H)⁺: m/z=514.1; Found:514.1.

Example 467.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((3S,6R)-6-(fluoromethyl)tetrahydro-2H-pyran-3-yl)-4-methylbenzenesulfonamide

Step 1. tert-Butyl((3S,6R)-6-(fluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate

A solution of tert-butyl((3S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate (0.040 g,0.17 mmol) [J Med. Chem. (2013), 56, 7396] in dichloromethane (1.7 mL)at −78° C. was treated with diethylaminosulfur trifluoride (0.046 mL,0.35 mmol) dropwise and stirred at room temperature for 5 h. Thereaction mixture was cooled back to −78° C., treated withdiethylaminosulfur trifluoride (0.046 mL, 0.35 mmol), and stirred atroom temperature for 14 h. The reaction mixture was cooled to 0° C.,quenched with saturated sodium bicarbonate (20 mL), and extracted withethyl acetate (30 mL). The organic layer was separated, washed withbrine, dried over sodium sulfate, filtered, and concentrated to aresidue. Purification by flash column chromatography using ethyl acetatein hexanes (0%-40%) gave the desired trans product (9.3 mg, 23%) as awhite solid. LCMS for C₁₁H₂₀FNO₃Na (M+Na)⁺: m/z=256.1; Found: 256.1.

Step 2. (3S,6R)-6-(Fluoromethyl)tetrahydro-2H-pyran-3-aminehydrochloride

The desired compound was prepared according to the procedure of Example465, step 3, using tert-butyl((3S,6R)-6-(fluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate as thestarting material. LCMS for C₆H₁₃FNO (M+H)⁺: m/z=134.1; Found: 134.1.

Step 3.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((3S,6R)-6-(fluoromethyl)tetrahydro-2H-pyran-3-yl)-4-methylbenzenesulfonamide

The desired compound was prepared according to the procedure of Example424, step 8, using (3S,6R)-6-(fluoromethyl)tetrahydro-2H-pyran-3-aminehydrochloride as the starting material. ¹H NMR (400 MHz, DMSO-d₆) δ 8.31(br s, 1H), 8.23 (br s, 1H), 8.05 (s, 1H), 7.93 (d, J=1.5 Hz, 1H),7.85-7.72 (m, 3H), 7.60 (d, J=8.1 Hz, 1H), 4.48-4.06 (m, 2H), 3.80-3.61(m, 1H), 3.54-3.35 (m, 1H), 3.15-2.90 (m, 2H), 2.33 (s, 3H), 1.84-1.68(m, 1H), 1.61-1.49 (m, 1H), 1.46-1.30 (m, 1H), 1.30-1.05 (m, 1H). LCMSfor C₁₈H₂₂FN₆O₃S (M+H)⁺: m/z=421.1; Found: 421.1.

Example 468.3-(4-Amino-2-methylimidazo[2,1-f][1,2,4]triazin-7-yl)-5-fluoro-N-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamide

Step 1. Ethyl 1-amino-1H-imidazole-2-carboxylate

A solution of ethyl 1H-imidazole-2-carboxylate (10.0 g, 71.4 mmol)[Combi-Blocks, SS-7811] in DMF (357 mL) was treated with potassiumtert-butoxide (74.9 mL, 74.9 mmol) dropwise and stirred at 20° C. for 1h. The reaction mixture was then treated with a solution ofO-(4-nitrobenzoyl)hydroxylamine (13.7 g, 74.9 mmol) inN,N-dimethylformamide (120 mL) dropwise via an addition funnel andstirred at 20° C. for 3 h. The reaction mixture was filtered and thesolid was washed with acetonitrile. The filtrate was evaporated to givethe crude product as a slightly oily red solid that was used withoutfurther purification.

Step 2. 2-Methylimidazo[2,1-f][1,2,4]triazin-4-ol

A solution of ethyl 1-amino-1H-imidazole-2-carboxylate (11.1 g, 71.4mmol) in acetonitrile (179 mL) in a 3-neck round bottom flask equippedwith a reflux condenser was cooled to 0° C. and bubbled with HCl gas for10 min. The reaction mixture was then stirred at 80° C. for 1 h. Thereaction mixture was concentrated and the resultant solid was trituratedwith diethyl ether to give crude intermediate amidine that was usedimmediately without further purification. A solution of crudeintermediate amidine in dioxane (179 mL) was treated carefully with 1.0M sodium bicarbonate in water (71.4 mL, 71.4 mmol) and stirred at 100°C. for 1 h. The reaction mixture was concentrated and the resultantsolid was diluted with acetonitrile and filtered to give the desiredproduct (15.1 g) as an off-white solid that used without furtherpurification (it is assumed that this material contains sodiumchloride). LCMS for C₆H₇N₄O (M+H)⁺: m/z=151.1; Found: 151.0.

Step 3. 7-Bromo-2-methylimidazo[2,1-f][1,2,4]triazin-4-ol

A suspension of 2-methylimidazo[2,1-f][1,2,4]triazin-4-ol (10.7 g, 71.4mmol) in DMF (238 mL) was treated with N-bromosuccinimide (15.3 g, 86.0mmol) and stirred at 80° C. for 1 h. The reaction mixture wasconcentrated and the residue was diluted with DCM, filtered, washed withadditional DCM, and dried to give the desired product (14.7 g) as awhite solid that was used without further purification (it is assumedthat this material contains sodium chloride from the previous step).LCMS for C₆H₆BrN₄O (M+H)⁺: m/z=229.0, 231.0; Found: 229.0, 230.9.

Step 4.7-Bromo-N-(4-methoxybenzyl)-2-methylimidazo[2,1-f][1,2,4]triazin-4-amine

A heterogeneous mixture of7-bromo-2-methylimidazo[2,1-f][1,2,4]triazin-4-ol (9.30 g, 40.6 mmol)and (benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate (31.1 g, 70.2 mmol) in DCE (203 mL) was treated with4-methoxybenzylamine (23.1 mL, 177 mmol) and DBU (4.41 mL, 29.2 mmol)and stirred at 20° C. for 20.5 h. The reaction mixture was treated withN,N-diisopropylethylamine (6.84 mL, 39.3 mmol) and stirred at 20° C. for67 h. The reaction mixture was filtered and washed with DCM. Thefiltrate was concentrated to give a crude orange oil. Purification byflash column chromatography using ethyl acetate in hexanes (0%-30%) gavethe desired product (4.80 g, 33.9%) as a yellow solid. LCMS forC₁₄H₁₅BrN₅O (M+H)⁺: m/z=348.0, 350.0; Found: 348.0, 350.0.

Step 5. 7-Bromo-2-methylimidazo[2,1-f][1,2,4]triazin-4-amine

A solution of7-bromo-N-(4-methoxybenzyl)-2-methylimidazo[2,1-f][1,2,4]triazin-4-amine(8.52 g, 24.5 mmol) in TFA (12.4 mL, 161 mmol) was stirred at 80° C. for18 h. The reaction mixture was treated with additional TFA (12.4 mL, 161mmol) and stirred at 80° C. for 5 h. The reaction mixture wasconcentrated and then diluted with toluene and re-concentrated (3×) togive 13.7 g of a crude green solid. The crude material was diluted withethyl acetate (82 mL) and stirred at 80° C. for 45 min. This materialdid not completely dissolve. The mixture was cooled to 20° C., dilutedwith hexanes (82 mL) over 5 min, and stirred overnight. The solids werefiltered and washed with hexanes to give the desired product (8.43g, >99%) as a green solid. LCMS for C₆H₇BrN₅ (M+H)⁺: m/z=228.0, 230.0;Found: 228.0, 230.0.

Step 6.3-Bromo-5-fluoro-N-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamide

The desired compound was prepared according to the procedure of Example466, step 2, using 1-amino-2-methylpropan-2-ol as the starting material.LCMS for C₁₁H₁₆BrFNO₃S (M+H)⁺: m/z=340.0, 342.0; Found: 340.0, 342.0.

Step 7.3-Fluoro-N-(2-hydroxy-2-methylpropyl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

The desired compound was prepared according to the procedure of Example1, step 2, using3-bromo-5-fluoro-N-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamideas the starting material. LCMS for C₁₇H₂₇BFNO₅SNa (M+Na)⁺: m/z=410.2;Found: 410.1.

Step 8.3-(4-Amino-2-methylimidazo[2,1-f][1,2,4]triazin-7-yl)-5-fluoro-N-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamide

The desired compound was prepared according to the procedure of Example1, step 3, using 7-bromo-2-methylimidazo[2,1-f][1,2,4]triazin-4-amineand3-fluoro-N-(2-hydroxy-2-methylpropyl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamideas the starting materials. ¹H NMR (500 MHz, DMSO-d₆) δ 8.22 (br s, 1H),8.15 (br s, 1H), 7.83-7.71 (m, 2H), 7.71-7.58 (m, 2H), 4.41 (s, 1H),2.69 (s, 2H), 2.28 (s, 3H), 2.21 (d, J=1.9 Hz, 3H), 1.06 (s, 6H). LCMSfor C17H₂₂FN₆O₃S (M+H)⁺: m/z=409.1; Found: 409.3.

Example 469.3-(4-Amino-2-(methyl-d₃)imidazo[2,1-f][1,2,4]triazin-7-yl)-5-fluoro-N-(2-hydroxy-2-methylpropyl)-4-(methyl-d₃)benzenesulfonamide

Step 1. 1-Amino-1H-imidazole-2-carbonitrile

The desired compound was prepared according to the procedure of Example468, step 1, using 1H-imidazole-2-carbonitrile [PharmaBlock, PBN2011278]as the starting material.

Step 2. 2-(Methyl-d₃)imidazo[2,1-f][1,2,4]triazin-4-amine

The desired compound was prepared according to the procedure of Example468, step 2, using 1-amino-1H-imidazole-2-carbonitrile andacetonitrile-d₃ as the starting materials. LCMS for C₆H₅D₃N₅(M+H)⁺:m/z=153.1; Found: 153.1.

Step 3. 7-Bromo-2-(methyl-d₃)imidazo[2,1-f][1,2,4]triazin-4-amine

The desired compound was prepared according to the procedure of Example468, step 3, using 2-(methyl-d₃)imidazo[2,1-f][1,2,4]triazin-4-amine asthe starting material. LCMS for C₆H₄D₃BrN₅ (M+H)⁺: m/z=231.0, 233.0;Found: 231.1, 233.1.

Step 4.2-(2-Fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A solution of 2-fluoro-1-iodo-4-nitrobenzene (1.96 g, 7.34 mmol),bis(pinacolato)diboron (1.86 g, 7.34 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.599 g, 0.734 mmol), and potassium acetate(2.38 g, 24.2 mmol) in DMSO (14.7 mL) in a seal-able tube was degassedwith nitrogen for 15 min, sealed, and stirred at 100° C. for 2.5 h. Thereaction mixture was cooled to room temperature, diluted with water andethyl acetate, and filtered over Celite. The aqueous layer was separatedand re-extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over magnesium sulfate, filtered, andconcentrated to a brown oil. Purification by flash column chromatographyusing ethyl acetate in hexanes (0%-20%) gave the desired product (1.60g, 81.6%).

Step 5. 2-Fluoro-1-(methyl-d₃)-4-nitrobenzene

A solution of2-(2-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.920 g, 3.45 mmol) and cesium fluoride (1.83 g, 12.1 mmol) in DMF(10.6 mL) and water (2.12 mL) in a seal-able tube was treated withiodomethane-d₃ (1.07 mL, 17.2 mmol), degassed with nitrogen for 5 min,and treated withbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(0.061 g, 0.086 mmol). The reaction mixture was degassed with nitrogenfor another 5 min, sealed, and heated at 45° C. for 21 h. The reactionmixture was cooled to room temperature, diluted with water and ethylacetate, and filtered over Celite. Three layers were observed duringseparation. The dark middle layer was filtered again over Celite andcombined with the other filtrate. The aqueous layer was separated andre-extracted with ethyl acetate (2×). The combined organic layers werewashed with brine, dried over sodium sulfate, filtered, and concentratedto an oil. Purification by flash column chromatography using ethylacetate in hexanes (0%-10%) gave the desired product (303 mg, 55.6%).

Step 6. 1-Bromo-3-fluoro-2-(methyl-d)-5-nitrobenzene

A solution of 2-fluoro-1-(methyl-d₃)-4-nitrobenzene (0.303 g, 1.92 mmol)in sulfuric acid (1.72 mL) and water (0.19 mL) was treated with silversulfate (0.299 g, 0.958 mmol) followed by bromine (0.099 mL, 1.92 mmol),and stirred at room temperature for 16 h. The reaction mixture wastreated with additional bromine (0.099 mL, 1.92 mmol) and stirred atroom temperature for 22 h. The reaction mixture was treated withadditional silver sulfate (0.299 g, 0.958 mmol) followed by bromine(0.050 mL, 0.958 mmol) and stirred at room temperature for 3 days. Thereaction mixture was poured into ice water, diluted with ethyl acetate,warmed to room temp, and filtered to remove solids. The solids werewashed with water and ethyl acetate. The layers were separated and theaqueous layer was extracted with ethyl acetate (3×). The combinedorganic layers were washed with brine, dried over magnesium sulfate,filtered, and concentrated to an amber oil. Purification by flash columnchromatography using ethyl acetate in hexanes (0%-10%) gave the desiredproduct (496 mg, 109%).

Step 7. 3-Bromo-5-fluoro-4-(methyl-d₃)aniline

A solution of 1-bromo-3-fluoro-2-(methyl-d₃)-5-nitrobenzene (0.454 g,1.92 mmol) in ethanol (7.98 mL) was treated with concentrated HCl (2.23mL, 26.8 mmol) followed by tin(II) chloride (1.09 g, 5.75 mmol) andstirred at room temperature for 15 h. The reaction mixture was filteredto remove solids and the filtrate was quenched with 1 N NaOH until themixture reached pH 10. There were salts that precipitated and thismixture was diluted with ethyl acetate and filtered over Celite. Theaqueous layer from the filtrate was separated and re-extracted withethyl acetate (2×). The combined organic layers were washed with brine,dried over magnesium sulfate, filtered, and concentrated to an oil.Purification by flash column chromatography using ethyl acetate inhexanes (0%-20%) gave the desired product (32.0 mg, 8.07%). LCMS forC₇H₅D₃BrFN (M+H)⁺: m/z=207.0, 209.0; Found: 206.9, 209.0.

Step 8. 3-Bromo-5-fluoro-4-(methyl-d₃)benzenesulfonyl chloride

The desired compound was prepared according to the procedure of Example466, step 1, using 3-bromo-5-fluoro-4-(methyl-d₃)aniline as the startingmaterial.

Step 9.3-Bromo-5-fluoro-N-(2-hydroxy-2-methylpropyl)-4-(methyl-d₃)benzenesulfonamide

The desired compound was prepared according to the procedure of Example466, step 2, using 3-bromo-5-fluoro-4-(methyl-d₃)benzenesulfonylchloride and 1-amino-2-methylpropan-2-ol as the starting materials. LCMSfor C₁₁H₁₂D₃BrFNO₃SNa (M+Na)⁺: m/z=365.0, 367.0; Found: 364.9, 367.0.

Step 10.3-Fluoro-N-(2-hydroxy-2-methylpropyl)-4-(methyl-d₃)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

The desired compound was prepared according to the procedure of Example1, step 2, using3-bromo-5-fluoro-N-(2-hydroxy-2-methylpropyl)-4-(methyl-d₃)benzenesulfonamideas the starting material. LCMS for C₁₇H₂₄D₃BrFNO₅SNa (M+Na): m/z=413.2;Found: 413.2.

Step 11.3-(4-Amino-2-(methyl-d₃)imidazo[2,1-f][1,2,4]triazin-7-yl)-5-fluoro-N-(2-hydroxy-2-methylpropyl)-4-(methyl-d₃)benzenesulfonamide

The desired compound was prepared according to the procedure of Example1, step 3, using3-fluoro-N-(2-hydroxy-2-methylpropyl)-4-(methyl-d₃)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamideand 7-bromo-2-(methyl-d₃)imidazo[2,1-f][1,2,4]triazin-4-amine as thestarting materials. ¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (br s, 1H), 8.15(br s, 1H), 7.80-7.71 (m, 2H), 7.65 (dd, J=9.0, 1.7 Hz, 1H), 7.62 (s,1H), 4.41 (s, 1H), 2.68 (s, 2H), 1.05 (s, 6H). LCMS for C₁₇H₁₆D₆FN₆O₃S(M+H)⁺: m/z=415.2; Found: 415.1.

Example 470.3-(4-Amino-2-(hydroxymethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-5-fluoro-N-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamide

Step 1. 2-(Diethoxymethyl)imidazo[2,1-f][1,2,4]triazin-4-amine

A solution of 1-amino-1H-imidazole-2-carbonitrile (0.533 g, 4.93 mmol)in ethanol (7.0 mL) in a microwave vial was treated with a solution ofmethyl 2,2-diethoxyacetimidate (0.954 g, 5.92 mmol) in ethanol (2.9 mL)over 2-3 min and stirred at room temperature for 10 min. The reactionmixture was treated with triethylamine (0.687 mL, 4.93 mmol) over 1 minand heated in a microwave at 120° C. for 2 h. The reaction mixture wasconcentrated, diluted with DCM, and concentrated again. The residue wasdiluted with ethyl acetate and water. Brine was added to help with theemulsion. The aqueous layer was separated and extracted with ethylacetate. The combined organic layers were washed with brine, dried overmagnesium sulfate, filtered, and concentrated to a brown oil.Purification by flash column chromatography using methanol indichloromethane (0%-5%) gave the desired product (858 mg, 64.6%). LCMSfor C₁₀H₁₅N₅O₂Na (M+Na)⁺: m/z=260.1; Found: 260.1.

Step 2. 7-Bromo-2-(diethoxymethyl)imidazo[2,1-f][1,2,4]triazin-4-amine

The desired compound was prepared according to the procedure of Example468, step 3, using2-(diethoxymethyl)imidazo[2,1-f][1,2,4]triazin-4-amine as the startingmaterial. LCMS for C₁₀H₁₄BrN₅O₂Na (M+Na)⁺: m/z=338.0, 340.0; Found:338.1, 340.1.

Step 3. 4-Amino-7-bromoimidazo[2,1-f][1,2,4]triazine-2-carbaldehyde

A solution of7-bromo-2-(diethoxymethyl)imidazo[2,1-f][1,2,4]triazin-4-amine (0.250 g,0.791 mmol) in tetrahydrofuran (0.47 mL) was treated with 6 Nhydrochloric acid (1.11 mL) and stirred at 90° C. for 1 h. The reactionmixture was concentrated to give the desired product as a white solidthat was used without further purification. LCMS for C₆H₅BrN₅O (M+H)⁺:m/z=242.0, 244.0; Found: 242.0, 244.0.

Step 4. (4-Amino-7-bromoimidazo[2,1-f][1,2,4]triazin-2-yl)methanol

A solution of4-amino-7-bromoimidazo[2,1-f][1,2,4]triazine-2-carbaldehyde (0.191 g,0.789 mmol) in methanol (0.99 mL) was treated with sodium borohydride(0.060 g, 1.58 mmol) in portions at room temperature and stirred for 45min. The reaction mixture was quenched with saturated ammonium chloride,concentrated to remove methanol, and diluted with water and ethylacetate. The mixture was filtered. The aqueous layer of the filtrate wasseparated and extracted with ethyl acetate. The combined organic layerswere washed with brine, then dried over magnesium sulfate, filtered, andconcentrated to a yellow solid. This solid was dissolved in methanol(4-5 mL), stirred at 60° C. for 1 h, cooled to room temperature, andstirred for 105 min. The solids were isolated by filtration and washedwith methanol (1 mL) to give the desired product (54.0 mg, 28.0% for 2steps). LCMS for C₆H₇BrN₅O (M+H)⁺: m/z=244.0, 246.0; Found: 243.9,245.9.

Step 5.3-(4-Amino-2-(hydroxymethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-5-fluoro-N-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamide

The desired compound was prepared according to the procedure of example1, step 3, using3-fluoro-N-(2-hydroxy-2-methylpropyl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamideand (4-amino-7-bromoimidazo[2,1-f][1,2,4]triazin-2-yl)methanol as thestarting materials. ¹H NMR (400 MHz, DMSO-d₆) δ 8.29 (br s, 1H), 8.22(br s, 1H), 7.78 (s, 1H), 7.75 (s, 1H), 7.70-7.64 (m, 1H), 7.61 (s, 1H),5.15 (t, J=6.3 Hz, 1H), 4.41 (s, 1H), 4.31 (d, J=6.3 Hz, 2H), 2.68 (s,2H), 2.20 (d, J=2.0 Hz, 3H), 1.06 (s, 6H). LCMS for C₁₇H₂₂FN₆O₄S (M+H)⁺:m/z=425.1; Found: 425.1.

Example 471.N-(3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)tetrahydro-2H-pyran-4-sulfonamide

Step 1.N-(4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-4-sulfonamide

The desired compound was prepared according to the procedure of Example466, step 2, using tetrahydro-2H-pyran-4-sulfonyl chloride [AurumPharmatech, Z-2491] and4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [BoronMolecular, BM139] as the starting materials. LCMS for C₁₈H₂₈BNO₅SNa(M+Na): m/z=404.2; Found: 404.1.

Step 2.N-(3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)tetrahydro-2H-pyran-4-sulfonamide

The desired compound was prepared according to the procedure of example1, step 3, usingN-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-4-sulfonamideand 3-bromoimidazo[1,2-a]pyrazin-8-amine as the starting materials. ¹HNMR (400 MHz, DMSO-d₆) δ 9.90 (br s, 1H), 7.60 (s, 1H), 7.37 (d, J=8.4Hz, 1H), 7.28 (dd, J=8.2, 2.3 Hz, 1H), 7.25-7.16 (m, 3H), 6.96 (s, 2H),3.97-3.75 (m, 2H), 3.49-3.13 (m, 3H), 2.11 (s, 3H), 1.94-1.80 (m, 2H),1.75-1.51 (m, 2H). LCMS for C₁₈H₂₂N₅O₃S (M+H)⁺: m/z=388.1; Found: 388.1.

Example 472.(1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidin-3-yl)methanol

Step 1. 5-(Trifluoromethyl)pyrazin-2-amine

2-Chloro-5-(trifluoromethyl)pyrazine (5.0 g, 27 mmol) (Oakwood Products,075803) was stirred in ammonium hydroxide (190 mL, 2.7 mol) and heatedto 80° C. for 3.5 h in a sealed pressure vessel. After cooling to rt,the aqueous mixture was extracted with DCM (4 x). The extracts werecombined, dried over sodium sulfate, filtered, and concentrated toafford the title compound as a white solid (4.0 g, 90%). ¹H NMR (400MHz, CDCl₃) δ 8.34 (s, 1H), 8.01 (s, 1H), 5.01 (br s, 2H). LCMS forC₈H₅F₃N₃ (M+H)⁺: calculated m/z=164.0; found 164.1.

Step 2. 3-Cloro-5-(trifluoromethyl)pyrazin-2-amine

5-(Trifluoromethyl)pyrazin-2-amine (4.56 g, 28.0 mmol) was stirred inNMP (135 mL, 1400 mmol) and N-chlorosuccinimide (3.73 g, 28.0 mmol) wasadded. The reaction mixture was stirred at rt for 6 h. The reactionmixture was poured into sat. sodium thiosulfate (100 mL) and dilutedwith water (500 mL). The mixture was extracted with ethyl acetate (4×200mL). The combined extracts were washed with brine (3×), dried oversodium sulfate, filtered, and concentrated. Purification via silica gelcolumn (0-35% EtOAc/hexanes) afforded the title compound as a whitesolid (2.32 g, 42.0%). LCMS for C₅H₄ClF₃N₃(M+H)⁺: calculated m/z=198.0;found 198.0.

Step 3. 8-Chloro-6-(trifluoromethyl)imidazo[1,2-a]pyrazine

To a solution of 3-chloro-5-(trifluoromethyl)pyrazin-2-amine (2.32 g,11.7 mmol) in EtOH (84 mL) was slowly added chloroacetaldehyde (37.3 mL,294 mmol, 50% in H₂O). The reaction mixture was portioned into seven20-mL microwave vials, and then each was heated at 150° C. for 20 min ina microwave reactor. The reaction mixtures were combined andconcentrated, the residue was diluted with DCM, and triethylamine wasadded cautiously to adjust pH≥7. Purification via silica gelchromatography (0-50% EtOAc/hexanes) afforded the title compound as abrown oil (1.93 g, 74.2%). LCMS for C₇H₄ClF₃N₃(M+H)⁺: calculatedm/z=222.0; found 221.9.

Step 4. 3-Bromo-8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyrazine

To a solution of 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyrazine(0.37 g, 1.7 mmol) in DMF (11 mL) was added N-bromosuccinimide (0.30 g,1.7 mmol). The reaction mixture was heated at 60° C. for 2 h. Thereaction mixture was cooled to rt and poured into 40% sat. Na₂S₂O₃ (50mL). The aqueous mixture was then extracted with DCM (3×40 mL). Thecombined organic layers were washed with brine (75 mL), dried overNa₂SO₄, filtered, and concentrated. Purification via silica gelchromatography (10-40% EtOAc/hexanes) afforded the title compound as awhite solid (0.41 g, 82%). LCMS for C₇H₃BrClF₃N₃(M+H)⁺: calculatedm/z=299.9, 301.9; found 299.9, 301.8.

Step 5.3-Bromo-N-(4-methoxybenzyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine

A mixture of 3-bromo-8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyrazine(0.35 g, 1.2 mmol), N,N-diisopropylethylamine (0.40 mL, 2.3 mmol), and4-methoxybenzylamine (0.17 mL, 1.3 mmol) in iPrOH (5.0 mL) was heated at110° C. for 15 min in a microwave. The resulting white suspension waswashed with water (3 x). The resulting white solid was dried in vacuoovernight to afford the title compound as a white solid (0.53 g, >99%).¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (t, J=6.0 Hz, 1H), 7.97 (s, 1H), 7.80(s, 1H), 7.32 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 4.59 (d, J=6.0Hz, 2H), 3.70 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ−66.99. LCMS forC₁₅H₁₃BrF₃N₄O (M+H)⁺: calculated m/z=401.0, 403.0; found 401.0, 403.0.

Step 6. 3-Bromo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine

A solution of3-bromo-N-(4-methoxybenzyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine(0.53 g, 1.2 mmol) in TFA (2.9 mL) was heated at 55° C. for 1 h. Thereaction mixture was concentrated and then diluted with water (3.0 mL).With the reaction vial in a 0° C. bath, the aqueous mixture was basifiedwith 1.0 M NaOH (7.5 mL). The bath was removed, and the aqueous mixturewas stirred for 5 min. The resulting white precipitate was collected viafiltration, washed with water (2×10 mL) and dried to afford the crudeproduct as a white solid (0.440 g). Purification via silica gelchromatography (5-40% EtOAc/DCM) afforded the title compound as a whitesolid (0.25 g, 77%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (s, 1H), 7.81 (s,1H), 7.73 (br s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ−66.77. LCMS forC₇H₅BrF₃N₄(M+H)⁺: calculated m/z=281.0, 283.0; found 280.9, 282.9.

Step 7. 3-(o-Tolyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine

A mixture of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.52 g, 0.64 mmol), o-tolylboronic acid (1.4 g,10 mmol), and 3-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine(1.0 g, 3. 6 mmol) in THF (36 mL) and 1.0 M potassium carbonate in water(18 mL, 18 mmol) was degassed with N₂ for 5 min and then heated at 80°C. for 5 h. The reaction mixture was filtered through Celite, rinsingwith EtOAc and water. The resulting mixture was washed with water (2×75mL) and brine (70 mL). The organic layer was then dried over sodiumsulfate, filtered, and concentrated. Purification via silica gelchromatography (1-88% EtOAc/hexanes) afforded the title compound as awhite solid (1.1 g, >99% yield). LCMS for C₁₄H₁₂F₃N₄ (M+H)⁺: calculatedm/z=293.1; found 293.1.

Step 8.3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylbenzenesulfonylchloride

A 45-mL scintillation vial was charged with3-(o-tolyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine (0.49 g,1.7 mmol). The vial was placed under nitrogen, and dichloromethane (20mL) was added. The reaction vial was placed in an ice bath, andchlorosufluric acid (1.1 mL, 17 mmol) added over 2 min. After 5 min, theice bath was removed; the mixture was warmed to rt and then heated at50° C. for 3 h. The reaction mixture was again cooled to 0° C., and anadditional portion of chlorosufluric acid (1.1 ml, 17 mmol) was addedover 1 min. The mixture was warmed to rt and then heated at 50° C. for3.5 h. The reaction mixture was cooled to rt and diluted with DCM (20mL). The mixture added slowly to a stirred mixture of ice water (100 mL)and DCM (80 mL). The organic layer was removed, and the aqueous layerwas extracted with DCM (2×100 mL). The combined organic layers weredried over MgSO₄, filtered, and concentrated to afford the titlecompound as an orange-brown solid (0.53 g, 82%). LCMS forC₁₄H₁₁ClF₃N₄O₂S (M+H)⁺: calculated m/z=391.0; found 391.0.

Step 9.(1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidin-3-yl)methanol

To a mixture of piperidin-3-ylmethanol (3.0 μL, 0.027 mmol),triethylamine (11 μL, 0.080 mmol), and DMAP (0.3 mg, 3 μmol) in DMA(0.24 mL) at 0° C. was added3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylbenzenesulfonylchloride (10 mg, 0.027 mmol) in a single portion. The reaction mixturewas allowed to come to rt and stirred for 2 h. The reaction mixture wasagain cooled to 0° C., and the reaction was quenched with MeOH.Purification via preparative HPLC on a C-18 column (pH 10, 32-52%MeCN/0.1% NH₄OH (aq) over 5 min, 60 mL/min) afforded the desired productas a white solid (7.0 mg, 56%). ¹H NMR (600 MHz, DMSO-d₆) δ 7.84 (s,1H), 7.78 (dd, J=8.2, 1.9 Hz, 1H), 7.74-7.70 (m, 3H), 7.67 (br s, 2H),4.55 (t, J=5.3 Hz, 1H), 3.66 (dd, J=11.4, 3.7 Hz, 1H), 3.53 (d, J=10.9Hz, 1H), 3.37-3.25 (m, 1H), 3.23-3.09 (m, 1H), 2.37-2.30 (m, 1H), 2.30(s, 3H), 2.08 (t, J=10.8 Hz, 1H), 1.73-1.61 (m, 2H), 1.62-1.56 (m, 1H),1.55-1.42 (m, 1H), 1.01-0.83 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆)δ−66.70. LCMS for C₂₀H₂₃F₃N₅O₃S (M+H)⁺: calculated m/z=470.1; found470.2.

Example 473.3-(2-Methyl-5-(methylsulfonyl)phenyl)-6-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrazin-8-aminetrifluoroacetate

Step 1.6-Bromo-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-amine

A mixture of 6-bromo-3-iodoimidazo[1,2-a]pyrazin-8-amine (680 mg, 2.0mmol), bis(pinacolato)diboron (490 mg, 1.7 mmol), andtetrakis(triphenylphosphine)palladium(0) (120 mg, 0.10 mmol) in ethanol(10 mL) and 2.0 M Na₂CO₃ in water (1.7 mL, 3.3 mmol) was degassed for 5min with N₂. The reaction mixture was then heated in a microwave reactorat 130° C. for 20 min. The precipitated solid was collected viafiltration, washed with MeOH, and air dried to yield the title compound(620 mg, 74%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.96 (dd, J=8.0, 2.0 Hz, 1H),7.90 (d, J=1.9 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.69 (s, 1H), 7.59 (s,2H), 7.40 (s, 1H), 3.26 (s, 3H), 2.25 (s, 3H). LCMS for C₁₄H14BrN₄O₂S(M+H)⁺: calculated m/z=381.0, 383.0; found 381.0, 383.0.

Step 2.3-(2-Methyl-5-(methylsulfonyl)phenyl)-6-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrazin-8-aminetrifluoroacetate

A 1-dram vial was charged with6-bromo-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-amine(8 mg, 0.02 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (3 mg, 4 μmol), and (3-methylpyridin-4-yl)boronicacid (11 mg, 0.084 mmol). THF (0.42 mL) and then 1.0 M potassiumcarbonate (53 μL, 0.052 mmol) were added. The reaction mixture wasdegassed with N₂ briefly and then heated at 80° C. for 16 h. Thereaction mixture was diluted with MeOH and filtered through a plug ofNa₂SO₄ and Celite. Purification via preparative HPLC on a C-18 column(pH 2, 11-31% MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded thetitle compound as a yellow semi-solid (3.7 mg, 34%). ¹H NMR (500 MHz,DMSO-d₆) δ 8.72 (s, 1H), 8.67 (d, J=5.7 Hz, 1H), 8.00-7.94 (m, 2H),7.89-7.82 (m, 2H), 7.72 (d, J=8.8 Hz, 1H), 7.70 (s, 1H), 7.60 (br s,2H), 3.25 (s, 3H), 2.52 (s, 3H), 2.33 (s, 3H). LCMS for C₂₀H₂₀N₅O₂S(M+H)⁺: calculated m/z=394.1; found 394.1.

Examples 474 to 486 were synthesized according to procedures analogousto the synthesis of Example 473, and the data are listed in Table 20.

TABLE 20

LCMS Ex. Name R⁸ [M + H]⁺ No. ¹H NMR Spectra 4742-(3-(8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-6-yl)phenyl) acetonitrile trifluoroacetate

418.1 475 6-(4-(Difluoromethyl)phenyl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8- amine trifluoroacetate

429.1 476 6-(3-Fluoropyridin-4-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8- amine trifluoroacetate

398.1 ¹H NMR (500 MHz, DMSO-d₆) δ 8.60 (d, J = 3.3 Hz, 1H), 8.52 (dd, J= 5.0, 1.0 Hz, 1H), 8.06 (dd, J = 7.0, 5.0 Hz, 1H), 7.99 (d, J = 6.9 Hz,2H), 7.84 (d, J = 1.0 Hz, 2H), 7.76 (d, J = 9.3 Hz, 1H), 7.52 (s, 2H),3.26 (s, 3H), 2.32 (s, 3H). 477 6-(2-Methoxypyridin-3-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8- amine trifluoroacetate

410.0 478 6-(2-Fluoro-6-methoxyphenyl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8- amine trifluoroacetate

427.2 479 6-(1-Methyl-1H-pyrazol-5-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8- amine trifluoroacetate

383.1 480 4-(8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-6-yl)-3-fluoro-N,N- dimethylbenzamide

468.1 481 (3-(8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-6-yl)-2-fluorophenyl)methanol

427.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.98 (dd, J = 8.1, 2.0 Hz, 1H), 7.95(d, J = 1.9 Hz, 1H), 7.92 (td, J = 7.8, 1.9 Hz, 1H), 7.79-7.72 (m, 2H),7.59 (s, 1H), 7.47-7.40 (m, 1H), 7.30- 7.22 (m, 3H), 5.25 (t, J = 5.5Hz, 1H), 4.55 (d, J = 5.5 Hz, 2H), 3.26 (s, 3H), 2.29 (s, 3H). 4826-(6-Aminopyridin-3-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8- amine trifluoroacetate

395.1 483 6-(3-Fluoro-2-methoxypyridin-4-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8- amine trifluoroacetate

428.1 484 6-(3-Chloropyridin-4-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8- amine trifluoroacetate

414.0 485 6-(3-Methoxypyridin-4-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8- amine trifluoroacetate

410.1 486 2-(3-(8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-6-yl)phenoxy) acetonitrile trifluoroacetate

434.2

Example 487.6-(2-Fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-amine

Step 1.4-(8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-6-yl)-3-fluorobenzaldehyde

The title compound was synthesized according to experimental procedureanalogous to the synthesis of Example 473, Step 1, substituting(2-fluoro-4-formylphenyl)boronic acid for (3-methylpyridin-4-yl)boronicacid. Purification via silica gel chromatography (12-100% EtOAc in DCM)afforded a yellow-orange solid (16 mg), which contained the titlecompound as a 3:2 mixture with an aldehyde byproduct. This material wascarried forward without further purification. LCMS for C₂₁H₁₈FN₄O₃S(M+H)⁺: calculated m/z=425.1; found 425.0.

Step 2.6-(2-Fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-amine

To a mixture of4-(8-amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-6-yl)-3-fluorobenzaldehyde(15 mg, 0.025 mmol, 70% purity) and pyrrolidine (6 μL, 0.07 mmol) inMeOH (0.5 mL) and acetic acid (0.7 μL) was added sodium cyanoborohydride(6 mg, 0.1 mmol). The reaction mixture was stirred overnight. Thereaction was quenched with water. Purification via prep LCMS viapreparative HPLC on a C-18 column (pH 10, MeCN/0.1% NH₄OH (aq)) affordedthe desired product title compound as white solid (2.5 mg, 21%). LCMSfor C₂₅H₂₇FN₅O₂S (M+H)⁺: calculated m/z=480.2; found 480.2.

Example 488.1-(4-(8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-6-yl)-3-fluorophenyl)ethan-1-ol

Step 1. 1-(4-Bromo-3-fluorophenyl)ethan-1-ol

To a solution of 4-bromo-3-fluorobenzaldehyde (0.50 g, 2.5 mmol) in THF(10 mL) at −44° C. was added methylmagnesium bromide (0.99 mL, 3.0 mmol.3.0 M in Et₂O). The reaction mixture was allowed to warm to rt, stirringfor 3 h. The reaction was quenched with sat. NH₄Cl. The resulting aq.suspension was extracted with EtOAc (3 x). The combined organic layerswere dried over MgSO₄, filtered, and concentrated. Purification viasilica gel chromatography (25-69% EtOAc/hexanes) afforded the desiredproduct as a clear liquid (0.51 g, 95%). ¹H NMR (400 MHz, CDCl₃) δ 7.50(apparent t, J=8.0 Hz, 1H), 7.16 (d, J=9.5 Hz, 1H), 7.02 (d, J=8.4 Hz,1H), 4.87 (q, J=6.5 Hz, 1H), 1.47 (d, J=6.4 Hz, 3H). ¹⁹F NMR (376 MHz,CDCl₃) δ−107.10.

Step 2.1-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-ol

A mixture of 1-(4-bromo-3-fluorophenyl)ethan-1-ol (0.13 g, 0.59 mmol),bis(pinacolato)diboron (0.17 g, 0.65 mmol), potassium acetate (0.17 g,1.8 mmol), and bis(triphenylphosphine)palladium(II) chloride (15 mg,0.022 mmol) in THF (4.6 mL) was degassed with N₂ for 5 min. The mixturewas then heated at 140° C. in a microwave for 20 min. The reactionmixture was diluted with EtOAc and filtered through Celite, rinsing withEtOAc. The filtrate was washed with water and then brine, dried overNa₂SO₄, filtered, and concentrated. Purification via silica gelchromatography (1-10% MeOH in DCM) afforded a grey-brown solid (0.19 g).This material was a mixture of the title compound and anotherfluorinated impurity; it was carried on without further purification.LCMS for C₁₄H₁₉BFO₂ (M−OH)⁺: calculated m/z=249.2; found 249.2.

Step 3.1-(4-(8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-6-yl)-3-fluorophenyl)ethan-1-ol

The title compound was synthesized according to experimental procedureanalogous to the synthesis of Example 473, Step 1, substituting1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-olfor (3-methylpyridin-4-yl)boronic acid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.02(d, J=8.2 Hz, 1H), 8.00-7.98 (m, 1H), 7.98-7.95 (m, 1H), 7.77-7.72 (m,2H), 7.62 (s, 1H), 7.25 (dd, J=8.5, 1.6 Hz, 1H), 7.23 (br s, 2H), 7.17(dd, J=13.2, 1.6 Hz, 1H), 5.29 (d, J=4.4 Hz, 1H), 4.85-4.64 (m, 1H),3.26 (s, 3H), 2.31 (s, 3H), 1.32 (d, J=6.5 Hz, 3H). LCMS forC₂₂H₂₂FN₄O₃S (M+H)⁺: calculated m/z=441.1; found 441.1.

Example 489.6-(5-Fluoro-2-methylpyridin-4-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-aminetrifluoroacetate

A mixture of 4-bromo-5-fluoro-2-methylpyridine (16 μL),bis(pinacolato)diboron (40 mg, 0.16 mmol), KOAc (39 mg, 0.395 mmol), anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (4 mg, 5 μmol) in THF (0.37 mL) was degassed withN₂ for 3 min. The mixture was then heated at 140° C. in a microwave for20 min. The reaction mixture was diluted with EtOAc and filtered throughCelite, rinsing with EtOAc. The filtrate was washed with water and thenbrine, dried over Na₂SO₄, filtered, and concentrated to afford the crudeboronate ester.

A 1-dram vial was charged withdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (3 mg, 4 μmol) and6-bromo-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-amine(8 mg, 0.02 mmol). A solution containing a half portion of the crudeboronate ester in THF (0.50 mL) and then 1.0 M potassium carbonate (53μL, 0.052 mmol) were added. The reaction mixture was degassed with N₂for 5 min and then heated at 80° C. for 3 h. The reaction mixture waspartitioned between EtOAc and water. The organic layer was removed, andthe aqueous extracted with EtOAc (2×). The combined organic layers weredried over Na₂SO₄ and filtered. Purification via preparative HPLC on aC-18 column (pH 2, 14-34% MeCN/0.1% TFA (aq) over 5 min, 60 mL/min)afforded the title compound as a yellow solid (6 mg, 60%). LCMS forC₂₀H₁₉FN₅O₂S (M+H)⁺: calculated m/z=412.1; found 412.0.

Example 490.(5-(8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-6-yl)-6-methoxypyridin-2-yl)methanoltrifluoroacetate

Step 1. (5-Bromo-6-methoxypyridin-2-yl)methanol

To a suspension of methyl 5-bromo-6-methoxypicolinate (20 mg, 0.079mmol) (Ark Pharm, AK100459) in ethanol (0.25 mL) was added sodiumborohydride (9.6 mg, 0.25 mmol). The reaction mixture was then heated at50° C. for 2.5 h. An additional portion of sodium borohydride (10 mg,0.27 mmol) was added, and the reaction mixture was heated at 50° C. foran additional 2 h. The reaction was quenched with water, and thereaction mixture was partitioned between sat. NaHCO₃ and EtOAc. Theorganic layer was removed, and the aqueous mixture was extracted withEtOAc (2×). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered, and concentrated. Purification via silica gelchromatography (15-55% EtOAc/hexanes) afforded the desired product as awhite solid (11 mg, 64%). LCMS for C₇H₉BrNO₂ (M+H)⁺: calculatedm/z=218.0, 220.0; found 217.9, 220.1.

Step 2.(5-(8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-6-yl)-6-methoxypyridin-2-yl)methanoltrifluoroacetate

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 489, substituting(5-bromo-6-methoxypyridin-2-yl)methanol for4-bromo-5-fluoro-2-methylpyridine. LCMS for C₂₁H₂₂N₅O₄S (M+H)⁺:calculated m/z=440.1; found 440.1.

Example 491.6-(4-Methoxy-1H-pyrazol-5-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-aminetrifluoroacetate

Step 1. 3-Bromo-4-methoxy-1H-pyrazole

To a solution of 4-methoxy-1H-pyrazole (71 mg, 0.70 mmol) (Synthonix,M20056) in DMF (4.7 mL) was added N-bromosuccinimide (130 mg, 0.70mmol). After stirring at rt for 2 h, the reaction mixture was dilutedwith DCM and poured into sat. Na₂S₂O₃. The organic layer was removed,and the aqueous layer was extracted twice more with DCM. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated. Purification via silica gel chromatography (10-80%EtOAc/hexanes) afforded the title compound as a white solid (77 mg,62%). LCMS for C₄H6BrN₂O (M+H)⁺: calculated m/z=177.0, 179.0; found177.0, 178.9.

Step 2.3-Bromo-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole and5-Bromo-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

A solution of 3-bromo-4-methoxy-1H-pyrazole (77 mg, 0.44 mmol) in THF(5.4 mL) at 0° C. was treated with 2.0 M NaOtBu in THF (0.28 mL, 0.57mmol). Upon stirring at 0° C. for 30 min, the reaction mixture wastreated with (2-(chloromethoxy)ethyl)trimethylsilane (92 μL, 0.52 mmol)and was then stirred for 2 h during which the reaction mixture came tort. The reaction was quenched with sat. NH₄Cl and diluted with water.The aqueous mixture was extracted with EtOAc (3 x). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. Purificationvia silica gel chromatography (10-30% EtOAc in hexanes) afforded thetitle compounds as 1.3:1 mixture of regioisomers (130 mg, 95%, clearoil). ¹H NMR (400 MHz, CDCl₃) Major isomer: δ 7.16 (s, 1H), 5.29 (s,2H), 3.81 (s, 3H), 3.62-3.49 (m, 2H), 0.99-0.81 (m, 2H), −0.01 (s, 9H).Minor isomer: δ 7.38 (s, 1H), 5.42 (s, 2H), 3.85 (s, 3H), 3.62-3.49 (m,2H), 0.99-0.81 (m, 2H), −0.02 (s, 9H). LCMS for C₁₀H₂₀BrN₂O₂Si (M+H)⁺:calculated m/z=307.0, 309.0; found 306.9, 309.0.

Step 3.6-(4-Methoxy-1H-pyrazol-5-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-aminetrifluoroacetate

A mixture of3-bromo-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole and5-bromo-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (31mg, 0.10 mmol, mixture of two regioisomers), bis(pinacolato)diboron (32mg, 0.13 mmol), potassium acetate (32 mg, 0.33 mmol), anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (3 mg, 4 μmol) in THF (0.30 mL) was degassed withN₂ for 3 min. The mixture was then heated at 140° C. in a microwave for20 min and then again for 60 min. Additional portions ofbis(pinacolato)diboron (32 mg, 0.13 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (3 mg, 4 μmol) were added. The reaction mixturewas degassed briefly and then heated at 140° C. in a microwave for 20min. The reaction mixture was diluted with EtOAc and filtered throughCelite, rinsing with EtOAc. The filtrate was washed with water and thenbrine, dried over Na₂SO₄, filtered, and concentrated to afford the crudeboronate ester.

A 1-dram vial was charged with6-bromo-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-amine(8 mg, 0.02 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (3 mg, 4 μmol). A solution of the crude boronateester in THF (0.50 mL) and then 1.0 M potassium carbonate (53 μL, 0.052mmol) were added. The reaction mixture was degassed with N₂ for 5 minand then heated at 80° C. for 16 h. The reaction mixture was partitionedbetween EtOAc and water. The organic layer was removed, and the aqueouslayer was extracted with EtOAc (2×). The combined organic layers werewashed with brine, filtered through a plug of Na₂SO₄, and concentrated.

The resulting residue was dissolved in 1:1 DCM/trifluoroacetic acid(0.80 mL) and heated at 40° C. for 1 h. After cooling to rt, thereaction mixture was diluted with MeOH. Purification via preparativeHPLC on a C-18 column (pH 2, 19-35% MeCN/0.1% TFA (aq) over 5 min, 60mL/min) afforded the title compound as a white solid (2 mg, 10%). ¹H NMR(400 MHz, CD₃OD) δ 8.13-8.05 (m, 2H), 7.93 (s, 1H), 7.83 (s, 1H), 7.79(d, J=8.6 Hz, 1H), 7.55 (s, 1H), 3.81 (s, 3H), 3.20 (s, 3H), 2.42 (s,3H). LCMS for C₁₈H₁₉N₆O₃S (M+H)⁺: calculated m/z=399.1; found 399.1.

Example 492.7-(2-Methyl-5-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-aminetrifluoroacetate

Step 1. Sodium 3-bromo-4-methylbenzenesulfinate

To a mixture of sodium sulfite (0.94 g, 7.4 mmol) and sodium bicarbonate(0.62 g, 7.4 mmol) in water (3.1 mL) at 85° C. was added3-bromo-4-methylbenzenesulfonyl chloride (0.50 g, 1.9 mmol). Sodiumbicarbonate (0.623 g, 7.42 mmol) and then a second portion of3-bromo-4-methylbenzenesulfonyl chloride (0.52 g, 1.9 mmol) was added tothe reaction mixture. [Note: Evolution of CO₂ was observed.] Thereaction mixture was stirred at 85° C. for 0.5 h before it wasconcentrated. The resulting solid was triturated with EtOH (4 x, 50 mLtotal). The filtrate was concentrated to afford a white solid (0.99g, >99%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.57 (d, J=1.7 Hz, 1H), 7.34-7.23(m, 2H), 2.32 (s, 3H). LCMS for C₇H₈BrO₂S (M+2H)⁺: calculated m/z=234.9,236.9; found 235.0, 237.0.

Step 2. 4-(((3-Bromo-4-methylphenyl)sulfonyl)methyl)tetrahydro-2H-pyran

To a solution of sodium 3-bromo-4-methylbenzenesulfinate (50 mg, 0.19mmol) in DMF (1 mL) was added 4-(bromomethyl)tetrahydro-2H-pyran (26μL). The reaction mixture was stirred at 50° C. overnight. An additionalportion of 4-(bromomethyl)tetrahydro-2H-pyran (26 μL) was added, and thereaction mixture was stirred at 50° C. for 1 d. The reaction mixture wasdiluted with water, and the aqueous mixture was extracted with EtOAc(3×). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered, and concentrated. Purification via silica gelchromatography (20-80% EtOAc/hexanes) afforded the title compound as awhite solid (32 mg, 49%). ¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=2.0 Hz,1H), 7.73 (dd, J=8.0, 1.9 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 3.93 (dd,J=12, 2.4 Hz, 2H), 3.41 (td, J=11.7, 1.9 Hz, 2H), 3.01 (d, J=6.4 Hz,2H), 2.49 (s, 3H), 2.37-2.19 (m, 1H), 1.87-1.75 (m, 2H), 1.53-1.35 (m,2H). LCMS for C₁₃H₁₈BrO₃S (M+H)⁺: calculated m/z=333.0, 335.0; found333.0, 335.0.

Step 3.4,4,5,5-Tetramethyl-2-(2-methyl-5-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)-1,3,2-dioxaborolane

A mixture of4-(((3-bromo-4-methylphenyl)sulfonyl)methyl)tetrahydro-2H-pyran (32 mg,0.096 mmol), bis(pinacolato)diboron (32 mg, 0.13 mmol), potassiumacetate (32 mg, 0.33 mmol), anddichlorobis(triphenylphosphine)palladium(II) (3 mg, 4 μmol) in THF (0.3mL) was degassed briefly with N₂. The mixture was heated in a microwaveat 140° C. for 20 min. The reaction mixture was diluted with EtOAc andfiltered through Celite, rinsing with EtOAc. The filtrate was washedwith water and then brine, dried over Na₂SO₄, filtered, and concentratedto afford the title compound as a crude product, which was utilizedwithout further purification. LCMS for C₁₉H₃₀BO₅S (M+H)⁺: calculatedm/z=381.2; found 381.2.

Step 4.7-(2-Methyl-5-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-aminetrifluoroacetate

A 1-dram vial was charged with7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine (17 mg, 0.079 mmol),4,4,5,5-tetramethyl-2-(2-methyl-5-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)-1,3,2-dioxaborolane(crude product from Step 3), anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (13 mg, 0.016 mmol). THF (1.3 mL) and then 1.0 Mpotassium carbonate (160 μL, 0.16 mmol) were then added. The reactionmixture was degassed with N₂ for 5 min and then heated at 80° C.overnight. The reaction mixture was diluted with MeOH and filteredthrough a plug of Na₂SO₄ and Celite. Purification via preparative HPLCon a C-18 column (pH 2, 17-37% MeCN/0.1% TFA (aq) over 5 min, 60 mL/min)afforded the title compound as a white solid (23 mg, 58%). ¹H NMR (400MHz, DMSO-d₆) δ 8.39 (br s, 1H), 8.29 (br s, 1H), 8.09 (s, 1H), 8.01 (d,J=2.0 Hz, 1H), 7.89 (dd, J=8.1, 2.0 Hz, 1H), 7.83 (s, 1H), 7.68 (d,J=8.1 Hz, 1H), 3.82-3.70 (m, 2H), 3.32 (d, J=6.4 Hz, 2H), 3.27 (td,J=11.7, 2.1 Hz, 2H), 2.36 (s, 3H), 2.04 (ttd, J=10.7, 6.3, 3.1 Hz, 1H),1.68 (dd, J=12.9, 1.9 Hz, 2H), 1.32 (dtd, J=13.2, 11.4, 4.3 Hz, 2H).LCMS for C₁₈H₂₂N₅O₃S (M+H)⁺: calculated m/z=388.1; found 388.0.

Example 493.7-(2-Methyl-5-((3,3,3-trifluoropropyl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-aminetrifluoro acetate

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 492, substituting1,1,1-trifluoro-3-iodopropane for 4-(bromomethyl)tetrahydro-2H-pyran instep 2. LCMS for C₁₅H₁₅F₃N₅O₂S (M+H)⁺: calculated m/z=386.1; found386.0.

Example 494.4-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)butan-2-ol

Step 1. 4-((3-Bromo-4-methylphenyl)sulfonyl)butan-2-one

A mixture of sodium 3-bromo-4-methylbenzenesulfinate (0.20 g, 0.78 mmol)and but-3-en-2-one (70 μL, 0.86 mmol) in AcOH (0.18 mL) and water (1.8mL) was heated overnight at 110° C. After cooling to rt, the reactionmixture was diluted with water. The aqueous mixture was extracted withEtOAc (3×). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered, and concentrated to afford the title compound asa white solid (0.19 g, 80%). ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J=1.9Hz, 1H), 7.73 (dd, J=8.0, 1.9 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 3.41-3.32(m, 2H), 2.97-2.88 (m, 2H), 2.49 (s, 3H), 2.19 (s, 3H). LCMS forC₁₁H₁₄BrO₃S (M+H)⁺: calculated m/z=305.0, 307.0; found 304.9, 306.9.

Step 2. 4-((3-Bromo-4-methylphenyl)sulfonyl)butan-2-ol

Sodium borohydride (2.78 mg, 0.073 mmol) was added to a solution of4-((3-bromo-4-methylphenyl)sulfonyl)butan-2-one (16 mg, 0.052 mmol) in1:1 MeOH/THF (1.4 mL) at 0° C. The reaction mixture was stirred for 1.5h at 0° C. The reaction was quenched with water (0.3 mL). The reactionmixture was warmed to rt, and sat. NaHCO₃ was added. The aqueous mixturewas extracted with EtOAc (3×). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered, and concentrated. Purificationvia silica gel chromatography (10-40% EtOAc in DCM) afforded the titlecompound as a white residue (15 mg, 93%). LCMS for C₁₁H₁₆BrO₃S (M+H)⁺:calculated m/z=307.0, 309.0; found 307.0, 309.0.

Step 3.4-((4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)butan-2-ol

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 492, Step 3,substituting 4-((3-bromo-4-methylphenyl)sulfonyl)butan-2-ol for4-(((3-bromo-4-methylphenyl)sulfonyl)methyl)tetrahydro-2H-pyran. LCMSfor C₁₇H₂₈BO₅S (M+H)⁺: calculated m/z=355.2; found 355.2.

Step 4.4-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)butan-2-ol

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 492, Step 4,substituting 3-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-aminefor 7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine and substituting4-((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)butan-2-olfor4,4,5,5-tetramethyl-2-(2-methyl-5-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)-1,3,2-dioxaborolane.¹H NMR (600 MHz, DMSO-d₆) δ 7.94 (dd, J=8.1, 2.0 Hz, 1H), 7.91 (d, J=1.9Hz, 1H), 7.83 (s, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.68 (br s, 3H), 4.63 (d,J=4.7 Hz, 1H), 3.62 (s, 1H), 3.41-3.28 (m, 2H), 2.28 (s, 3H), 1.70-1.50(m, 2H), 1.02 (d, J=6.2 Hz, 3H). LCMS for C₁₈H₂₀F₃N₄O₃S (M+H)⁺:calculated m/z=429.1; found 429.2.

Example 495.4-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)-2-methylbutan-2-ol

Step 1. 4-((3-Bromo-4-methylphenyl)sulfonyl)-2-methylbutan-2-ol

Methylmagnesium bromide (40 μL, 0.1 mmol, 3 M in Et₂O) was addeddropwise to a solution of4-((3-bromo-4-methylphenyl)sulfonyl)butan-2-one (12 mg, 0.039 mmol) inTHF (1.0 mL) at −78° C. The reaction mixture was stirred overnightduring which it came to rt. The reaction mixture was cooled to 0° C.,and the reaction was quenched with NH₄Cl and water. The mixture wasextracted with EtOAc (3×). The organic layers were filtered through aplug of Na₂SO₄, combined, and concentrated to afford the title compound(8.2 mg, 65%). ¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=1.9 Hz, 1H), 7.73(dd, J=8.0, 2.0 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 3.28-3.19 (m, 2H), 2.49(s, 3H), 1.91-1.83 (m, 2H), 1.23 (s, 6H). LCMS for C₁₂H16BrO₂S (M-OH)⁺:calculated m/z=303.0, 305.0; found 303.0, 305.0.

Step 2.2-Methyl-4-((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)butan-2-ol

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 492, Step 3 substituting4-((3-bromo-4-methylphenyl)sulfonyl)-2-methylbutan-2-ol for4-(((3-bromo-4-methylphenyl)sulfonyl)methyl)tetrahydro-2H-pyran. LCMSfor C₁₈H₂₈BO₄S (M-OH)⁺: calculated m/z=351.2; found 351.1.

Step 4.4-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)-2-methylbutan-2-ol

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 492, Step 4,substituting 3-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-aminefor 7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine and substituting2-methyl-4-((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)butan-2-olfor4,4,5,5-tetramethyl-2-(2-methyl-5-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)-1,3,2-dioxaborolane.¹H NMR (400 MHz, DMSO-d₆) δ 7.98-7.89 (m, 2H), 7.83 (s, 1H), 7.74 (d,J=8.0 Hz, 1H), 7.68 (s, 3H), 4.42 (s, 1H), 3.40-3.20 (m, 2H), 2.28 (s,3H), 1.73-1.58 (m, 2H), 1.05 (s, 6H). LCMS for C₁₉H₂₂F₃N₄O₃S (M+H)⁺:calculated m/z=443.1; found 443.1.

Example 496.1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)propan-2-oltrifluoroacetate

Step 1. 1-((3-Bromo-4-methylphenyl)sulfonyl)propan-2-one

A mixture of sodium 3-bromo-4-methylbenzenesulfinate (20 mg, 0.078 mmol)and chloroacetone (6.5 μL, 0.078 mmol) in DMF (230 μL) was heated at100° C. for 5 min in a microwave. The reaction mixture was diluted withwater. The aqueous mixture was extracted with EtOAc (3×). The organiclayers were filtered through a plug of Na₂SO₄, combined, andconcentrated to afford the title compound (15 mg, 64%). ¹H NMR (400 MHz,CDCl₃) δ 8.04 (s, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H),4.15 (s, 2H), 2.49 (s, 3H), 2.41 (s, 3H). LCMS for C₁₀H₁₅BrNO₃S(M+NH₄)⁺: calculated m/z=308.0, 310.0; found 308.0, 310.0.

Step 2. 1-((3-Bromo-4-methylphenyl)sulfonyl)propan-2-ol

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 494, Step 2,substituting 1-((3-bromo-4-methylphenyl)sulfonyl)propan-2-one for4-((3-bromo-4-methylphenyl)sulfonyl)butan-2-one. ¹H NMR (400 MHz, CDCl₃)δ 8.08 (s, 1H), 7.75 (d, J=7.7 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 4.33 (s,1H), 3.36-3.05 (m, 3H), 2.50 (s, 3H), 1.26 (d, J=6.3 Hz, 3H). LCMS forC₁₀H₁₄BrO₃S (M+H)⁺: calculated m/z=293.0, 295.0; found 293.0, 294.9.

Step 3.1-((4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)propan-2-ol

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 492, Step 3 substituting1-((3-bromo-4-methylphenyl)sulfonyl)propan-2-ol for4-(((3-bromo-4-methylphenyl)sulfonyl)methyl)tetrahydro-2H-pyran. LCMSfor C₁₆H₂₆BO₅S (M+H)⁺: calculated m/z=341.2; found 341.1.

Step 4.1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)propan-2-oltrifluoroacetate

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 492, Step 4,substituting 3-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-aminefor 7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine and substituting1-((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)propan-2-olfor4,4,5,5-tetramethyl-2-(2-methyl-5-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)-1,3,2-dioxaborolane.LCMS for C₁₇H₁₈F₃N₄O₃S (M+H)⁺: calculated m/z=415.1; found 415.2.

Example 497.1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)propan-2-ol

Step 1. Sodium3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfinate

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 492, Step 1,substituting3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonylchloride for 3-bromo-4-methylbenzenesulfonyl chloride. LCMS forC₁₂H₁₂N₅O₂S (M+2H): calculated m/z=290.1; found 290.0.

Step 2.1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)propan-2-ol

To a solution of sodium3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfinate(15 mg, 0.048 mmol) in DMF (240 μL) was added (bromomethyl)cyclobutane(5.4 μL, 0.048 mmol). The reaction mixture was stirred at 50° C.overnight. The reaction mixture was diluted with MeOH and filtered.Purification via preparative HPLC on a C-18 column (pH 10, 33-55%MeCN/0.1% NH₄OH (aq) over 5 min, 60 mL/min) afforded the title compoundas a white solid (7.5 mg, 44%). LCMS for C₁₇H₂₀N₅O₂S (M+H)⁺: calculatedm/z=358.1; found 358.2.

Example 498.cis-4-(((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)methyl)cyclohexan-1-ol

To a solution of sodium3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfinate(17 mg, 0.055 mmol) in DMF (0.27 mL) was addedcis-(4-(bromomethyl)cyclohexyloxy)(tert-butyl)dimethylsilane (17 mg,0.055 mmol) (prepared as described by Liu, J. et al. ACS Med. Chem.Lett. 2012, 3, 129). The reaction mixture was stirred at 50° C.overnight. After cooling to rt, an additional portion ofcis-(4-(bromomethyl)cyclohexyloxy)(tert-butyl)dimethylsilane (17 mg,0.055 mmol) in DMF (0.10 mL) was added, and the reaction mixture wasstirred at 50° C. for 1 d. The reaction mixture was diluted with water.The aqueous mixture was extracted with EtOAc (3×). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated to afford the unpurified TBS-protected intermediate (31mg). LCMS for C₂₅H₃₈N₅O₃SSi (M+H)⁺: calculated m/z=516.2; found 516.2.

This crude product was dissolved in MeOH (2.5 mL), and conc. HCl (0.23mL, 2.7 mmol, 12 M) was added. The reaction mixture was stirred at rtfor 3 h and then concentrated. Purification via preparative HPLC on aC-18 column (pH 2, 21-33% MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) andthen repurification via preparative HPLC on a C-18 column (pH 10, 20-40%MeCN/0.1% NH₄OH (aq) over 5 min, 60 mL/min) afforded the title compound(1.3 mg, 5.9%). LCMS for C₁₉H₂₄N₅O₃S (M+H)⁺: calculated m/z=402.2; found402.1.

Examples 499 to 500 were synthesized according to procedures analogousto the synthesis of Example 492, and the data are listed in Table 21.

TABLE 21

LCMS Ex. Name R⁸ [M + H]⁺ No. NMR Spectra 4997-(5-((Cyclopropylmethyl)sulfonyl)-2-methylphenyl) imidazo[2,1-f][1,2,4]triazin-4-amine

344.1 500 7-(5-(((3,3-Difluorocyclobutyl)methyl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine

394.1

Example 501.cis-3-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)cyclohexan-1-ol

A mixture of sodium3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfinate(50 mg, 0.16 mmol) and cyclohex-2-en-1-one (17 μL, 0.18 mmol) in AcOH(37 μL) and water (370 μL) was heated 1 d at 110° C. After cooling tort, the reaction mixture was diluted with water. The aqueous mixture wasextracted with EtOAc (3×). The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated to afford the crudeketone intermediate. LCMS for C₁₈H₂₀N₅O₃S (M+H)⁺: calculated m/z=386.1;found 386.1.

The crude ketone intermediate was dissolved in 1:1 iPrOH/THF (4.0 mL),and the solution was cooled to 0° C. Sodium borohydride (8.5 mg, 0.23mmol) was then added, and the reaction mixture was stirred for 1 h at 0°C. The reaction was quenched with H₂O (1 mL). Purification viapreparative HPLC on a C-18 column (pH 10, 18-38% MeCN/0.1% NH₄OH (aq)over 5 min, 60 mL/min) afforded the title compound as a white solid (17mg, 27%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.06 (s, 1H), 8.02 (s, 2H), 7.94(d, J=2.0 Hz, 1H), 7.81 (dd, J=8.0, 2.0 Hz, 1H), 7.79 (s, 1H), 7.67 (d,J=8.2 Hz, 1H), 4.58 (d, J=4.8 Hz, 1H), 3.47-3.35 (m, 1H), 3.29-3.21 (m,1H), 2.38 (s, 3H), 2.11 (d, J=12.2 Hz, 1H), 1.88 (d, J=11.5 Hz, 1H),1.78 (d, J=12.7 Hz, 2H), 1.34-1.11 (m, 3H), 1.10-0.94 (m, 1H). LCMS forC₁₈H₂₂N₅O₃S (M+H)⁺: calculated m/z=388.1; found 388.1.

Example 502.3-((3-(8-Amino-6-(2-methoxypyridin-3-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)-3-methylbutan-2-oltrifluoroacetate

Step 1. 3-((3-Bromo-4-methylphenyl)sulfonyl)-3-methylbutan-2-one

To a mixture of 1-((3-bromo-4-methylphenyl)sulfonyl)propan-2-one (70 mg,0.24 mmol) (from Example 496, Step 1) and potassium carbonate (73 mg,0.53 mmol) in DMF (2.4 mL) was added iodomethane (37 μL, 0.60 mmol). Thereaction mixture was stirred at rt for 2 h. The reaction mixture wasdiluted with water, and the aqueous mixture was extracted with EtOAc(3×). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered, and concentrated. Purification via silica gelchromatography (1-50% EtOAc/hexanes) afforded the title compound as awhite solid (42 mg, 55%). ¹H NMR (400 MHz, CDCl₃) δ 7.92 (d, J=1.9 Hz,1H), 7.57 (dd, J=8.0, 1.9 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 2.49 (s, 6H),1.55 (s, 6H). LCMS for C₁₂H₁₅BrNaO₃S (M+Na)⁺: calculated m/z=341.0,343.0; found 340.9, 342.9.

Step 2. 3-((3-Bromo-4-methylphenyl)sulfonyl)-3-methylbutan-2-ol

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 494, Step 2,substituting 3-((3-bromo-4-methylphenyl)sulfonyl)-3-methylbutan-2-onefor 4-((3-bromo-4-methylphenyl)sulfonyl)butan-2-one. LCMS forC₁₂H₁₈BrO₃S (M+H)⁺: calculated m/z=321.0, 323.0; found 321.0, 323.0.

Step 3.3-Methyl-3-((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)butan-2-ol

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 492, Step 3 substituting3-((3-bromo-4-methylphenyl)sulfonyl)-3-methylbutan-2-ol for4-(((3-bromo-4-methylphenyl)sulfonyl)methyl)tetrahydro-2H-pyran. LCMSfor C₁₈H₃₀BO₅S (M+H)⁺: calculated m/z=369.2; found 369.2.

Step 4.3-((3-(8-Amino-6-(2-methoxypyridin-3-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)-3-methylbutan-2-oltrifluoroacetate

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 40, Step 2, substituting3-methyl-3-((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)butan-2-olfor4,4,5,5-tetramethyl-2-[2-methyl-5-(methylsulfonyl)phenyl]-1,3,2-dioxaborolaneand substituting (2-methoxypyridin-3-yl)boronic acid for(2-fluorophenyl)boronic acid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (s, 1H),8.21 (dd, J=4.9, 1.9 Hz, 1H), 7.96-7.83 (m, 4H), 7.71 (d, J=8.1 Hz, 1H),7.14 (dd, J=7.5, 4.9 Hz, 1H), 4.04-3.93 (m, 1H), 3.88 (s, 3H), 2.36 (s,3H), 1.19 (d, J=4.1 Hz, 6H), 1.10 (d, J=6.3 Hz, 3H). LCMS forC₂₄H₂₈N₅O₄S (M+H)⁺: calculated m/z=482.2; found 482.1.

Example 503.1-(((3-(8-Amino-6-(3-fluoropyridin-4-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)methyl)cyclobutan-1-ol

Step 1. 1-(((3-Bromo-4-methylphenyl)sulfonyl)methyl)cyclobutan-1-ol

To a solution of 2-bromo-1-methyl-4-(methylsulfonyl)benzene (50 mg, 0.20mmol) in THF (1.0 mL) at −78° C. was added dropwise n-butyllithium (80μL, 0.20 mmol, 2.5 M in hexanes), and the reaction mixture was stirredat −78° C. for 30 min. The reaction mixture was then added dropwise to asolution of cyclobutanone (16 μL, 0.22 mmol) in THF (2.0 mL) at −78° C.After 10 min, the −78° C. bath was removed, and the reaction mixture wasstirred for 4 h, during which it came to rt. The reaction mixture wasthen cooled to 0° C., and the reaction was quenched with sat. NH₄Cl. Themixture was partitioned between water and DCM. The organic layer wasremoved, and the aqueous layer was extracted with DCM (2×). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated.Purification via preparative HPLC on a C-18 column (pH 2, 26-51%MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded the title compound asa white solid (11 mg, 14%). ¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J=1.9 Hz,1H), 7.76 (dd, J=7.9, 1.9 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 3.46 (s, 2H),2.50 (s, 4H), 2.37-2.07 (m, 3H), 2.04-1.78 (m, 1H), 1.78-1.49 (m, 1H).LCMS for C₁₂H₁₉BrNO₃S (M+NH₄)⁺: calculated m/z=336.0, 338.0; found336.0, 338.0.

Step 2.1-(((4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)methyl)cyclobutan-1-ol

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 492, Step 3,substituting 1-(((3-bromo-4-methylphenyl)sulfonyl)methyl)cyclobutan-1-olfor 4-(((3-bromo-4-methylphenyl)sulfonyl)methyl)tetrahydro-2H-pyran.LCMS for C₁₈H₂₆BO₄S (M−OH)⁺: calculated m/z=349.2; found 349.1.

Step 3.1-(((3-(8-Amino-6-(3-fluoropyridin-4-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)methyl)cyclobutan-1-ol

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 40, Step 2, substituting1-(((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)methyl)cyclobutan-1-olfor4,4,5,5-tetramethyl-2-[2-methyl-5-(methylsulfonyl)phenyl]-1,3,2-dioxaborolaneand substituting3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine for(2-fluorophenyl)boronic acid. LCMS for C₂₃H₂₃FN₅O₃S (M+H)⁺: calculatedm/z=468.1; found 468.1.

Example 504.3-(8-Amino-6-isopropylimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 38, substituting potassiumisopropenyltrifluoroborate for potassium vinyltrifluoroborate in Step 1.LCMS for C₂₂H₃₀N₅O₃S (M+H)⁺: calculated m/z=444.2; found 444.2.

Example 505.3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-4-methylbenzenesulfonamide

Step 1.N-((1r,4r)-4-Hydroxy-4-methylcyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 1, Steps 1 and 2, substitutingtrans-4-amino-1-methylcyclohexanol for trans-4-aminocyclohexanol inStep 1. LCMS for C₂₀H₃₃BNO₅S (M+H)⁺: calculated m/z=410.2; found 410.2.

Step 2. 3-Iodo-6-methylimidazo[1,2-a]pyrazin-8-amine

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 16, Steps 1 and 2, substituting8-bromo-6-methylimidazo[1,2-a]pyrazine (Frontier, B12886) for6,8-dibromoimidazo[1,2-a]pyrazine in Step 1. ¹H NMR (400 MHz, DMSO-d₆) δ7.58 (s, 1H), 7.38 (s, 1H), 6.95 (s, 2H), 2.23 (s, 3H). LCMS for C₇H₈IN₄(M+H)⁺: calculated m/z=275.0; found 275.0.

Step 3.3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-4-methylbenzenesulfonamide

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 1, Step 3, substitutingN-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamideforN-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamideand substituting 3-iodo-6-methylimidazo[1,2-a]pyrazin-8-amine for3-bromoimidazo[1,2-a]pyridin-8-amine. ¹H NMR (600 MHz, DMSO-d₆) δ 7.83(dd, J=8.1, 2.0 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.64 (d, J=8.2 Hz, 1H),7.61 (s, 1H), 7.60 (s, 1H), 7.00 (d, J=0.9 Hz, 1H), 6.98 (s, 2H), 4.12(s, 1H), 3.09 (s, 1H), 2.23 (s, 3H), 2.15 (d, J=0.8 Hz, 3H), 1.66-1.55(m, 2H), 1.52-1.43 (m, 2H), 1.32-1.17 (m, 4H), 1.05 (s, 3H). LCMS forC₂₂H₂₈N₅O₃S (M+H)⁺: calculated m/z=430.2; found 430.2.

Example 506.(S)-1-((3-(8-Amino-6-(2-fluoro-4-(hydroxymethyl)phenyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)pyrrolidin-3-ol

Step 1.(S)-1-((4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)pyrrolidin-3-ol

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 1, Steps 1 and 2, substituting(S)-pyrrolidin-3-ol for trans-4-aminocyclohexanol in Step 1. LCMS forC₁₇H₂₇BNO₅S (M+H)⁺: calculated m/z=368.2; found 368.1.

Step 2.(S)-1-((3-(8-Amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)pyrrolidin-3-ol

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 16, Step 3, substituting(S)-1-((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)pyrrolidin-3-olforN-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide.LCMS for C₁₇H₁₉BrN₅O₃S (M+H)⁺: calculated m/z=452.0, 454.0; found 452.1,454.1.

Step 3.(S)-1-((3-(8-Amino-6-(2-fluoro-4-(hydroxymethyl)phenyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)pyrrolidin-3-ol

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 17, substituting(S)-1-((3-(8-amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)pyrrolidin-3-olfor3-(8-amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamideand substituting (2-fluoro-4-(hydroxymethyl)phenyl)boronic acid for(2-methylphenyl)boronic acid. LCMS for C₂₄H₂₅FN₅O₄S (M+H)⁺: calculatedm/z=498.2; found 498.2.

Example 507.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1s,4s)-4-hydroxy-4-methylcyclohexyl-1-d)-4-methylbenzenesulfonamide

Step 1.(R)-2-Methyl-N-(8-deutero-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide

A mixture of 1,4-dioxaspiro[4.5]decan-8-one (2.5 g, 16 mmol),(R)-(+)-2-methyl-2-propanesulfinamide (1.9 g, 16 mmol), and titanium(IV)ethoxide (6.7 ml, 32 mmol) in THF (32 mL) was heated at reflux for 2 h.After cooling to rt, the reaction mixture was added dropwise via cannulato a suspension of sodium borodeuteride (2.0 g, 48 mmol) (Aldrich,205591) in THF (12 mL) at −44° C. The original flask, which hadcontained the reaction mixture from the imine condensation, was rinsedwith THF (2×6 mL), and this mixture was added dropwise to the flaskcontaining the sodium borodeuteride reaction mixture. The reactionmixture was then allowed to warm to rt, stirring for 3 h. The reactionmixture was cooled to 0° C., and the reaction quenched by dropwiseaddition of methanol (13 mL, 320 mmol). After stirring for 10 min, themixture was warmed to rt while stirring 30 min. The mixture was thendiluted with EtOAc (80 mL) and poured into brine (5 mL). The resultingslurry was stirred rapidly for 20 min. The slurry was filtered throughCelite, rinsing the filter cake generously with EtOAc. The filtrate wasthen concentrated. Purification via silica gel chromatography (3-7% MeOHin DCM) afforded the title compound as a white solid (3.8 g, 90%). ¹HNMR (400 MHz, CDCl₃) δ 3.94 (s, 4H), 3.00 (s, 1H), 2.05-1.90 (m, 2H),1.83-1.70 (m, 2H), 1.68-1.51 (m, 4H), 1.20 (s, 9H). LCMS for C₁₂H₂₃DNO₃S(M+H)⁺: calculated m/z=263.2; found 263.1.

Step 2. (R)-2-Methyl-N-(1-deutero-4-oxocyclohexyl)propane-2-sulfinamide

A solution of p-toluenesulfonic acid monohydrate (0.13 g, 0.71 mmol) inwater (4.9 mL) was added to a solution of((R)-2-methyl-N-(8-deutero-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide(3.7 g, 14 mmol) in acetone (9.8 mL). The reaction mixture was thenheated at 100° C. for 15 min in a microwave. The reaction mixture wasdiluted with EtOAc and washed with sat. NaHCO₃. The organic layer wasremoved, and the aqueous layer was extracted with EtOAc (2×). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification via silica gel chromatography (70-100% EtOAcin DCM, then 0-5% MeOH in EtOAc) afforded the title compound as anoff-white solid (2.3 g, 75%). ¹H NMR (400 MHz, CDCl₃) δ 3.12 (s, 1H),2.55-2.30 (m, 4H), 2.30-2.14 (m, 2H), 1.98-1.75 (m, 2H), 1.24 (s, 9H).LCMS for C₁₀H₁₉DNO₂S (M+H)⁺: calculated m/z=219.1; found 219.1.

Step 3. (R)—N-((1 r,4R)-4-hydroxy-4-methylcyclohexyl-1-d)-2-methylpropane-2-sulfinamide and(R)—N-((1s,4S)-4-hydroxy-4-methylcyclohexyl-1-d)-2-methylpropane-2-sulfinamide

To a solution of(R)-2-methyl-N-(1-deutero-4-oxocyclohexyl)propane-2-sulfinamide (1.0 g,4.6 mmol) in THF (46 mL) at −78° C. was added dropwise methyllithium(8.6 mL, 14 mmol, 1.6 M in diethyl ether). Upon addition, the reactionmixture was allowed to come to rt and was stirred for 3 h at rt. Thereaction mixture was cooled to 0° C., and the reaction was quenched withsat. NH₄Cl solution (20 mL). The bath was removed. After stirring for 5min, the mixture was then partitioned between water and EtOAc. Theorganic layer was removed, and the aqueous layer was extracted withEtOAc (2×). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated. Purification via silica gel chromatography(1-12% MeOH in DCM) afforded a mixture of the title compounds as a whitesolid (0.30 g). Repurification via preparative HPLC on a C-18 column (pH10, 14-28% MeCN/0.1% NH₄OH (aq) over 5 min, 60 mL/min) afforded theseparated isomers:(R)—N-((1r,4R)-4-hydroxy-4-methylcyclohexyl-1-d)-2-methylpropane-2-sulfinamide(first eluting, t_(R)=4.86 min, minor isomer) as white solid (53 mg,4.9%) and(R)—N-((1s,4S)-4-hydroxy-4-methylcyclohexyl-1-d)-2-methylpropane-2-sulfinamide(second eluting, t_(R)=5.62 min, major isomer) as a white solid (0.12 g,11%). First eluting: LCMS for C₁₁H₂₃DNO₂S (M+H)⁺: calculated m/z=235.2;found 235.2. Second eluting: ¹H NMR (400 MHz, CDCl₃) δ 3.04 (br s, 1H),1.91-1.78 (m, 2H), 1.76-1.34 (m, 8H), 1.23 (s, 3H), 1.20 (s, 9H). LCMSfor C₁₁H₂₃DNO₂S (M+H)⁺: calculated m/z=235.2; found 235.1.

Step 4. (1s,4s)-4-Amino-1-methylcyclohexan-4-d-1-ol hydrochloride

To a solution of(R)—N-((1s,4S)-4-hydroxy-4-methylcyclohexyl-1-d)-2-methylpropane-2-sulfinamide(10 mg, 0.043 mmol) in MeOH (0.50 mL) was added HCl (50 μL, 0.2 mmol,4.0 M in 1,4-dioxane) while the reaction flask was in a rt water bath.The bath was removed, and the reaction mixture was stirred at rt for 30min. The reaction mixture was concentrated to afford the title compound.¹H NMR (600 MHz, DMSO-d₆) δ 8.10 (s, 3H), 1.70-1.62 (m, 4H), 1.55 (d,J=11.7 Hz, 2H), 1.35-1.25 (m, 2H), 1.09 (s, 3H). LCMS for C₇H₁₅DNO(M+H)⁺: calculated m/z=131.1; found 131.2.

Step 5.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1s,4s)-4-hydroxy-4-methylcyclohexyl-1-d)-4-methylbenzenesulfonamide

To a solution of (1s,4s)-4-amino-1-methylcyclohexan-4-d-1-olhydrochloride (7.1 mg, 0.043 mmol), triethylamine (18 μL, 0.128 mmol),and DMAP (0.5 mg, 4 μmol) in DMA (350 μL) at 0° C. was added3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonylchloride (14 mg, 0.043 mmol) in a single portion. The reaction mixturewas allowed to come to rt, stirring for 2 h. The reaction mixture wasagain cooled to 0° C., and the reaction was quenched with MeOH.Purification via preparative HPLC on a C-18 column (pH 10, 26-38%MeCN/0.1% NH₄OH (aq) over 5 min, 60 mL/min) afforded the title compoundas a white solid (4.1 mg, 23%). LCMS for C₁₉H₂₄DN₆O₃S (M+H)⁺: calculatedm/z=418.2; found 418.1.

Example 508.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl-1-d)-4-methylbenzenesulfonamidetrifluoroacetate

Step 1. (1r, 4r)-4-Amino-1-methylcyclohexan-4-d-1-ol hydrochloride

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 507, Step 4 substituting(R)—N-((1r,4R)-4-hydroxy-4-methylcyclohexyl-1-d)-2-methylpropane-2-sulfinamide(from Example 507, Step 3) for(R)—N-((1s,4S)-4-hydroxy-4-methylcyclohexyl-1-d)-2-methylpropane-2-sulfinamide.LCMS for C₇H₁₅DNO (M+H)⁺: calculated m/z=131.1; found 131.1.

Step 2.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl-1-d)-4-methylbenzenesulfonamidetrifluoroacetate

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 507, Step 5 substituting(1r,4r)-4-amino-1-methylcyclohexan-4-d-1-ol hydrochloride for(1s,4s)-4-amino-1-methylcyclohexan-4-d-1-ol hydrochloride. ¹H NMR (500MHz, CD₃CN) δ 8.07 (s, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.83 (dd, J=8.1, 2.1Hz, 1H), 7.70 (s, 1H), 7.56 (d, J=8.1 Hz, 1H), 6.99 (br s, 2H), 5.66 (s,1H), 2.35 (s, 3H), 1.77-1.64 (m, 2H), 1.58-1.46 (m, 2H), 1.44-1.27 (m,4H), 1.12 (s, 3H). LCMS for C₁₉H₂₄DN₆O₃S (M+H)⁺: calculated m/z=418.2;found 418.2.

Example 509. Ethyl1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidine-3-carboxylate

Step 1. Ethyl1-((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperidine-3-carboxylate

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 1, Steps 1 and 2, substitutingethyl piperidine-3-carboxylate for trans-4-aminocyclohexanol in Step 1.LCMS for C₂₁H₃₃BNO₆S (M+H)⁺: calculated m/z=438.2; found 438.2.

Step 2. Ethyl1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidine-3-carboxylate

The title compound was synthesized according to an experimentalprocedure analogous to the synthesis of Example 1, Step 3, substitutingethyl1-((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperidine-3-carboxylateforN-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamideand substituting3-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine for3-bromoimidazo[1,2-a]pyridin-8-amine. LCMS for C₂₂H₂₅F₃N₅O₄S (M+H)⁺:calculated m/z=512.2; found 512.2.

Example 510.1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidine-3-carboxylicacid trifluoroacetate

To a solution of ethyl1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidine-3-carboxylate(22 mg, 0.043 mmol) in THF (0.31 mL) was added 1.0 M sodium hydroxide(95 μL, 0.095 mmol). The reaction mixture was stirred overnight at rt;diluted with MeOH, MeCN, and water; and filtered. Purification viapreparative HPLC on a C-18 column (pH 2, 33-53% MeCN/0.1% TFA (aq) over5 min, 60 mL/min) afforded the title compound as a white solid (7.7 mg,30%). LCMS for C₂₀H₂₁F₃N₅O₄S (M+H)⁺: calculated m/z=484.1; found 484.1.

Example 511.(1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidin-3-yl)((R)-2-(methoxymethyl)pyrrolidin-1-yl)methanone

To a mixture of (R)-2-(methoxymethyl)pyrrolidine (5 μL, 0.04 mmol),1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidine-3-carboxylicacid (10 mg, 0.021 mmol), andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (9.4 mg, 0.026 mmol) in DMF (0.20 mL) was addeddropwise N,N-diisopropylethylamine (5.0 μL, 0.029 mmol). The reactionmixture was stirred 1 h at rt. The reaction mixture was diluted withMeOH and purified via preparative HPLC on a C-18 column (pH 10, 35-55%MeCN/0.1% NH₄OH (aq) over 5 min, 60 mL/min) to afford the title compound(2.9 mg, 24%). LCMS for C₂₆H₃₂F₃N₆O₄S (M+H)⁺: calculated m/z=581.2;found 581.3.

Example 512. tert-Butyl((1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidin-3-yl)methyl)carbamate

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 472, Step 9 substitutingtert-butyl (piperidin-3-ylmethyl)carbamate for piperidin-3-ylmethanol.LCMS for C₂₅H₃₁F₃N₆NaO₄S (M+Na): calculated m/z=591.2; found 591.3.

Example 513.3-(5-((3-(Aminomethyl)piperidin-1-yl)sulfonyl)-2-methylphenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-aminetrifluoroacetate

A solution of tert-butyl((1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidin-3-yl)methyl)carbamate(40. mg, 0.070 mmol) in trifluoroacetic acid (1.1 mL) was stirred at rtfor 1 h. The reaction mixture was diluted with DCM and concentrated toafford the crude product. A quarter of the crude product was purifiedvia preparative HPLC on a C-18 column (pH 2, 36-56% MeCN/0.1% TFA (aq)over 5 min, 60 mL/min) to afford the title compound as a pink solid (13mg). LCMS for C₂₀H₂₄F₃N₆O₂S (M+H)⁺: calculated m/z=469.2; found 469.3.

Example 514.N-((1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidin-3-yl)methyl)-2-(dimethylamino)acetamide

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 511, substituting3-(5-((3-(aminomethyl)piperidin-1-yl)sulfonyl)-2-methylphenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-aminetrifluoroacetate for (R)-2-(methoxymethyl)pyrrolidine and substitutingdimethylglycine for1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidine-3-carboxylicacid. LCMS for C₂₄H₃₁F₃N₇O₃S (M+H)⁺: calculated m/z=554.2; found 554.1.

Example 515. tert-Butyl(1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidin-3-yl)carbamate

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 472, Step 9 substitutingtert-butyl (piperidin-3-ylmethyl)carbamate for piperidin-3-ylmethanol.LCMS for C₂₄H₂₉F₃N₆NaO₄S (M+Na)⁺: calculated m/z=577.2; found 577.1.

Example 516.3-(5-((3-Aminopiperidin-1-yl)sulfonyl)-2-methylphenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-aminetrifluoroacetate

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 513, substituting tert-butyl(1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidin-3-yl)carbamatefor tert-butyl((1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidin-3-yl)methyl)carbamate.LCMS for C₁₉H₂₂F₃N₆O₂S (M+H)⁺: calculated m/z=455.1; found 455.1.

Example 517.N-(1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidin-3-yl)cyclopropanecarboxamidetrifluoroacetate

The title compound was synthesized according to experimental proceduresanalogous to the synthesis of Example 511, substituting3-(5-((3-aminopiperidin-1-yl)sulfonyl)-2-methylphenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-aminetrifluoroacetate for (R)-2-(methoxymethyl)pyrrolidine and substitutingcyclopropanecarboxylic acid for1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidine-3-carboxylicacid. ¹H NMR (600 MHz, DMSO-d₆) δ 8.02 (d, J=7.6 Hz, 1H), 7.84 (s, 1H),7.79 (dd, J=8.0, 2.0 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.71 (d, J=8.2 Hz,1H), 7.69 (s, 1H), 7.66 (br s, 2H), 3.85-3.66 (m, 1H), 3.53-3.37 (m,1H), 3.37-3.27 (m, 1H), 2.63-2.54 (m, 1H), 2.35-2.26 (m, 1H), 2.29 (s,3H), 1.82-1.73 (m, 1H), 1.73-1.65 (m, 1H), 1.58-1.45 (m, 2H), 1.32-1.19(m, 1H), 0.72-0.57 (m, 4H). LCMS for C₂₃H₂₆F₃N₆O₃S (M+H)⁺: calculatedm/z=523.2; found 523.2.

Example 518.3-(8-Aminoimidazo[1,2-b]pyridazin-3-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-4-methylbenzenesulfonamide

Step 1. 3-Bromo-6-chloroimidazo[1,2-b]pyridazin-8-amine

The title compound was synthesized according to an experimentalprocedure analogous to Example 16, Step 2 substituting3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine (AstaTech, 50987) for6,8-dibromoimidazo[1,2-a]pyrazine. LCMS for C₆H₅BrClN₄ (M+H)⁺:calculated m/z=246.9, 248.9; found 247.0, 249.0.

Step 2.3-(8-Amino-6-chloroimidazo[1,2-b]pyridazin-3-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-4-methylbenzenesulfonamide

The title compound was synthesized according to an experimentalprocedure analogous to Example 1, Step 3, substituting3-bromo-6-chloroimidazo[1,2-b]pyridazin-8-amine for3-bromoimidazo[1,2-a]pyridin-8-amine and substitutingN-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamideforN-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide.LCMS for C₂₀H₂₅C1N₅O₃S (M+H)⁺: calculated m/z=450.1; found 450.2.

Step 3.3-(8-Aminoimidazo[1,2-b]pyridazin-3-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-4-methylbenzenesulfonamide

To a solution of3-(8-amino-6-chloroimidazo[1,2-b]pyridazin-3-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-4-methylbenzenesulfonamide(12 mg, 0.027 mmol) and triethylamine (7.4 μL, 0.053 mmol) in MeOH (0.43mL) under a N₂ atmosphere was added Pd/C (11 mg, 5.3 μmol, 10% Pd, ˜50%H2O) (Sigma-Aldrich 330108, lot 03014DC). The atmosphere was replacedwith H₂. After stirring overnight at rt, the reaction mixture wasfiltered through Celite, and the Celite pad was washed with MeOH. Thefiltrate was concentrated. Purification via preparative HPLC on a C-18column (pH 10, 23-37% MeCN/0.1% NH₄OH (aq) over 5 min, 60 mL/min)afforded the title compound as a white solid (3.0 mg, 27%). ¹H NMR (600MHz, DMSO-d₆) δ 7.97 (d, J=5.4 Hz, 1H), 7.92 (d, J=2.1 Hz, 1H), 7.75(dd, J=8.0, 2.1 Hz, 1H), 7.68 (s, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.04 (s,2H), 6.18 (d, J=5.4 Hz, 1H), 4.12 (s, 1H), 3.11-2.98 (m, 1H), 2.30 (s,3H), 1.66-1.56 (m, 2H), 1.48 (t, J=8.9 Hz, 2H), 1.34-1.20 (m, 4H), 1.05(s, 3H). LCMS for C₂₀H₂₆N₅O₃S (M+H)⁺: calculated m/z=416.1; found 416.2.

Example 519.3-(8-(Benzylamino)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamide

Step 1. 8-Chloro-3-iodo-6-(trifluoromethyl)imidazo[1,2-a]pyrazine

The title compound was synthesized according to an experimentalprocedure analogous to Example 472, Step 4, substitutingN-iodosuccinimide for N-bromosuccinimide. LCMS for C₇H₃ClF₃IN₃ (M+H)⁺:calculated m/z=347.9; found 347.9.

Step 2. N-Benzyl-3-iodo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine

The title compound was synthesized according to an experimentalprocedure analogous to Example 472, Step 5, substituting benzylamine for4-methoxybenzylamine and substituting8-chloro-3-iodo-6-(trifluoromethyl)imidazo[1,2-a]pyrazine for3-bromo-8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyrazine. LCMS forC₁₄H₁₁F₃₁N₄ (M+H)⁺: calculated m/z=419.0; found 419.0.

Step 3.N-(2-hydroxy-2-methylpropyl)-4-methyl-3-(4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

The title compound was synthesized according to experimental proceduresanalogous to Example 1, Steps 1 and 2, substituting1-amino-2-methylpropan-2-ol for trans-4-aminocyclohexanol in Step 1.LCMS for C₁₇H₂₇BNO₄S (M-OH)⁺: calculated m/z=352.2; found 352.1.

Step 4.3-(8-(Benzylamino)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamide

The title compound was synthesized according to an experimentalprocedure analogous to Example 1, Step 3, substitutingN-benzyl-3-iodo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine for3-bromoimidazo[1,2-a]pyridin-8-amine and substitutingN-(2-hydroxy-2-methylpropyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamideforN-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (t, J=6.3 Hz, 1H), 7.84 (d, J=8.0 Hz,1H), 7.81 (s, 2H), 7.65 (d, J=8.1 Hz, 1H), 7.62 (s, 1H), 7.51 (s, 1H),7.43 (d, J=7.4 Hz, 2H), 7.31 (t, J=7.6 Hz, 2H), 7.23 (t, J=7.3 Hz, 1H),4.70 (d, J=6.3 Hz, 2H), 4.38 (s, 1H), 2.65 (s, 2H), 2.25 (s, 3H), 1.04(s, 6H). LCMS for C₂₅H₂₇F₃N₅O₃S (M+H)⁺: calculated m/z=534.2; found534.1.

Example 520.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(5-cyanobicyclo[3.1.1]heptan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate

Step 1. tert-butyl (5-carbamoylbicyclo[3.1.1]heptan-1-yl)carbamate

A mixture of5-((tert-butoxycarbonyl)amino)bicyclo[3.1.1]heptane-1-carboxylic acid(40 mg, 0.157 mmol), ammonium carbonate (75 mg, 0.78 mmol), HATU (89 mg,0.24 mmol), and DIEA (0.055 mL, 0.31 mmol) in DCE (0.6 mL) was stirredat ambient temperature for 5 h. The reaction mixture was diluted withethyl acetate (20 mL) and water (3 mL). The layers were separated andthe organic layer was washed with water (3×3 mL) and the combinedaqueous phases were extracted with ethyl acetate (5 mL). The combinedorganic layers were washed with brine (5 mL), dried over Na₂SO₄,filtered and concentrated in-vacuo. The crude product was used directlyin the next step without further purification. LCMS for C₁₃H₂₂N₂O₃(M+Na)⁺: calculated m/z=277.3; found 277.2.

Step 2. 5-aminobicyclo[3.1.1]heptane-1-carbonitrile hydrochloride

To a 0° C. solution of tert-butyl(5-carbamoylbicyclo[3.1.1]heptan-1-yl)carbamate (40. mg, 0.16 mmol) andtrimethylamine (0.088 mL, 0.63 mmol) was added trifluoroacetic anhydride(0.027 mL, 0.19 mmol) and the resulting solution was stirred at ambienttemperature for 4 h. LCMS data indicated the presence of startingmaterial, so a second aliquot of trifluoroacetic anhydride (30 μL) wasadded and stirring was continued overnight. 4 N hydrogen chloride in1,4-dioxane (1.0 mL, 4.0 mmol) was added to the crude reaction mixtureto remove the Boc protecting group and the solution was stirredovernight. The volatiles were removed in-vacuo and the residue wasplaced under high vacuum and used in the next step without furtherpurification. LCMS for C₈H₁₂N₂(M+H)⁺: calculated m/z=137.2; found 137.1.

Step 3.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(5-cyanobicyclo[3.1.1]heptan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate

To a solution of 5-aminobicyclo[3.1.1]heptane-1-carbonitrilehydrochloride (8.4 mg, 0.049 mmol) and3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonylchloride (10 mg, 0.031 mmol) in DCM (0.5 mL) was added sequentiallytriethylamine (0.017 mL, 0.12 mmol), and DMAP (1.5 mg, 0.012 mmol).After 15 min., NMP (0.2 mL) was added and the resulting solution wasstirred at ambient temperature overnight. The crude reaction mixture wasdiluted with MeOH and acidified by the addition of a couple of drops of4 N HCl (aq) and purified by preparative HPLC on a C-18 column (pH 2,15-35% MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) to afford the titlecompound. LCMS for C₂₀H₂₁N₇O₂S (M+H)⁺: calculated m/z=424.5; found424.2.

Example 521.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(5-(1-hydroxyethyl)bicyclo[3.1.1]heptan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate

Step 1. tert-butyl(5-(methoxy(methyl)carbamoyl)bicyclo[3.1.1]heptan-1-yl)carbamate

A solution of5-((tert-butoxycarbonyl)amino)bicyclo[3.1.1]heptane-1-carboxylic acid(200 mg, 0.78 mmol), N, O-dimethylhydroxylamine hydrochloride (153 mg,1.57 mmol), HATU (357 mg, 0.94 mmol), and DIEA (0.274 mL, 1.57 mmol) inDCE (4 mL) was stirred at ambient temperature overnight. LCMS dataindicated that the major reaction component was the desired product. Thereaction mixture was diluted with EtOAc (50 mL) and H₂O (5 mL). Thelayers were separated and the organic layer was washed with H₂O (3×5 mL)and the combined aqueous phases were extracted with EtOAc (10 mL). Thecombined organic layers were washed with brine (5 mL), dried overNa₂SO₄, filtered, and concentrated in-vacuo. The crude product was useddirectly in the next step without any further purification. LCMS forC₁₅H₂₆N₂O₄ (M+Na)⁺: calculated m/z=321.4; found 321.2.

Step 2. 5-amino-N-methoxy-N-methylbicyclo[3.1.1]heptane-1-carboxamidehydrochloride

To a solution of tert-butyl(5-(methoxy(methyl)carbamoyl)bicyclo[3.1.1]heptan-1-yl)carbamate (145mg, 0.485 mmol) in THF was added 4 N HCl in 1,4-dioxane (2.0 mL, 8.0mmol) and the solution was stirred at ambient temperature for 4 h. Thevolatiles were removed in-vacuo and the residue was placed on the highvacuum and used in the next step without further purification. LCMS forC10H₁₈N₂O₂ (M+H)⁺: calculated m/z=199.3; found 199.2.

Step 3.5-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonamido)-N-methoxy-N-methylbicyclo[3.1.1]heptane-1-carboxamide

To a solution of5-amino-N-methoxy-N-methylbicyclo[3.1.1]heptane-1-carboxamidehydrochloride (115 mg, 0.49 mmol), triethylamine (0.172 mL, 1.24 mmol),and DMAP (3.8 mg, 0.031 mmol) in DCM (2 mL) was added3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonylchloride (100. mg, 0.309 mmol) and the resulting solution was stirred atambient temperature overnight. LCMS data indicated that some of theamine starting material was present, so a second aliquot of sulfonylchloride (40 mg) and DMAP (2 mg) were added and stirring was continuedovernight. LCMS data indicated that some of the amine starting materialwas present, so an additional aliquot of sulfonyl chloride (30 mg), Et₃N(100 μL), NMP (100 μL) and DMAP (2 mg) were added and stirring wascontinued for 3 h. The crude product was purified by CombiFlashchromatography (25 g silica gel column, eluting with 0-20%methanol/dichloromethane) to afford the desired product (62 mg, 42%).LCMS for C₂₂H₂₇N₇O₄S (M+H)⁺: calculated m/z=486.6; found 486.2.

Step 4.N-(5-acetylbicyclo[3.1.1]heptan-1-yl)-3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonamide

To a 0° C. solution of5-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonamido)-N-methoxy-N-methylbicyclo[3.1.1]heptane-1-carboxamide(62 mg, 0.128 mmol) in anhydrous THF (1. mL) was added 3 Mmethylmagnesium bromide in Et₂O (0.20 mL, 0.60 mmol) drop-wise and theresulting solution was allowed to gradually warm to ambient temperature.After 4 h, LCMS data indicated that the reaction was complete. The crudereaction mixture was cooled to 0° C. and quenched by the addition ofsaturated ammonium chloride (aq). The reaction mixture was diluted withEtOAc (30 mL) and washed successively with water (2×3 mL) and brine (2×3mL). The organic layer was dried over Na₂SO₄, filtered, and concentratedin-vacuo. The crude product was purified by CombiFlash chromatography(12 g silica gel column, eluting with 0-15% methanol/dichloromethane) toafford the desired product. LCMS for C₂₁H₂₄N₆O₃S (M+H)⁺: calculatedm/z=441.5; found 441.1.

Step 5.3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(5-(1-hydroxyethyl)bicyclo[3.1.1]heptan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate

To a solution ofN-(5-acetylbicyclo[3.1.1]heptan-1-yl)-3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonamide(18 mg, 0.041 mmol) in THF (1.0 mL) was added NaBH₄ (7.7 mg, 0.20 mmol)and the resulting mixture was stirred at ambient temperature overnight.LCMS data indicated that the major reaction component was the desiredproduct. The reaction mixture was diluted with MeOH and purified bypreparative HPLC on a C-18 column (pH 2, 18.7-36.7% MeCN/0.1% TFA (aq)over 12 min, 60 mL/min) to afford the title compound. LCMS forC₂₁H₂₆N₆O₃S (M+H)⁺: calculated m/z=443.5; found 443.2.

Example 522.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(5-(1-(3-cyanoazetidin-1-yl)ethyl)bicyclo[3.1.1]heptan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate

To a pre-stirred solution ofN-(5-acetylbicyclo[3.1.1]heptan-1-yl)-3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonamide(18 mg, 0.041 mmol, prepared in Example 521, Step 4),azetidine-3-carbonitrile hydrochloride (24 mg, 0.20 mmol), and Et₃N(0.028 mL, 0.20 mmol) was added sodium triacetoxyborohydride (14 mg,0.069 mmol) and the resulting solution was stirred at 60° C. overnight.The reaction mixture was diluted with MeOH and purified via preparativeHPLC on a C-18 column (pH 2, 12-30% MeCN/0.1% TFA (aq) over 12 min, 60mL/min) to afford the title compound. LCMS for C₂₅H₃₀N₅O₂S (M+H)⁺:calculated m/z=507.6; found 507.2.

Example 523.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-(3-methyl-3-azabicyclo[3.1.1]heptan-1-yl)benzenesulfonamidetrifluoroacetate

Step 1. 3-((benzyloxy)carbonyl)-3-azabicyclo[3.1.1]heptane-1-carboxylicacid

To a solution of 3-azabicyclo[3.1.1]heptane-1-carboxylic acid (0.522 g,3.70 mmol) and N-(benzyloxycarbonyloxy)succinimide (1.01 g, 4.07 mmol)in DCM (15 mL) was added DIEA (0.97 mL, 5.6 mmol) and the resultingsolution was stirred at ambient temperature overnight. The reactionmixture was diluted with dichloromethane (50 mL) and acidified by theaddition of 1 N HCl (aq) (10 mL). The layers were separated and theorganic layer was washed with H₂O (3×5 mL) and the combined aqueousphases were extracted with dichloromethane (10 mL). The combined organiclayers were washed with brine (10 mL), dried over Na₂SO₄, filtered, andconcentrated in-vacuo to afford an off-white solid (1.00 g, 98%). LCMSfor C₁₅H₁₇NO₄ (M+H)⁺: calculated m/z=276.3; found 276.1.

Step 2. benzyl1-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.1]heptane-3-carboxylate

To a solution of3-((benzyloxy)carbonyl)-3-azabicyclo[3.1.1]heptane-1-carboxylic acid(150 mg, 0.545 mmol) and triethylamine (0.091 mL, 0.65 mmol) intert-butanol (3.0 mL) was added diphenyl phosphoryl azide (0.129 mL,0.599 mmol) and the solution was heated at 85° C. in a sealed vialovernight. LCMS data indicated that the major reaction component was thedesired product. The crude reaction mixture was concentrated in-vacuoand the residue was purified by CombiFlash chromatography (25 g column,eluting with 0-50% ethyl acetate/hexanes) to afford the desired product(45 mg, 24%). LCMS for C₁₉H₂₆N₂O₄ (M+Na)⁺: calculated m/z=369.4; found369.1.

Step 3. benzyl 1-amino-3-azabicyclo[3.1.1]heptane-3-carboxylatehydrochloride

To a solution of benzyl1-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.1]heptane-3-carboxylate(45 mg, 0.130 mmol) in THF (1 mL) was added 4 N HCl in 1,4-dioxane (2mL, 8.00 mmol) and the solution was stirred at ambient temperature for 2h. The volatiles were removed in-vacuo and the residue was placed underhigh vacuum prior to using in the subsequent reaction. LCMS forC₁₄H₁₈N₂O₂ (M+H)⁺: calculated m/z=247.3; found 247.2.

Step 4. benzyl1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonamido)-3-azabicyclo[3.1.1]heptane-3-carboxylate

To a solution of benzyl 1-amino-3-azabicyclo[3.1.1]heptane-3-carboxylatehydrochloride (34 mg, 0.12 mmol), Et₃N (0.069 mL, 0.49 mmol), and DMAP(1.5 mg, 0.012 mmol) in DCM (0.5 mL) was added3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonylchloride (40. mg, 0.12 mmol) and the resulting mixture was stirred atambient temperature overnight. The crude reaction mixture was purifiedby CombiFlash chromatography (12 g silica gel column, eluting with 0-15%methanol/dichloromethane) to afford the desired product (18 mg, 27%).LCMS for C₂₆H₂₇N₇O₄S (M+H)⁺: calculated m/z=534.6; found 534.1.

Step 5.3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3-azabicyclo[3.1.1]heptan-1-yl)-4-methylbenzenesulfonamide

A mixture of benzyl1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonamido)-3-azabicyclo[3.1.1]heptane-3-carboxylate(18 mg, 0.034 mmol) and 10% palladium (dry basis) on activated carbon,wet, Degussa type E101 NE/W (4 mg) in MeOH (3 mL) was stirred for 16 hunder an atmosphere of hydrogen. The crude reaction mixture was purgedwith nitrogen, diluted with EtOAc (20 mL), and filtered through a pad ofcelite. The inorganics were washed thoroughly with EtOAc. The volatileswere removed in-vacuo and the crude product was used in the subsequentstep without further purification. LCMS for C₁₈H₂₁N₇O₂S (M+H)⁺:calculated m/z=400.5; found 400.1.

Step 6.3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-(3-methyl-3-azabicyclo[3.1.1]heptan-1-yl)benzenesulfonamidetrifluoroacetate

A mixture of3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3-azabicyclo[3.1.1]heptan-1-yl)-4-methylbenzenesulfonamide(14 mg, 0.035 mmol), paraformaldehyde (2.1 mg, 0.070 mmol), and sodiumtriacetoxyborohydride (15 mg, 0.070 mmol) in DCE (0.6 mL) was stirred atambient temperature for 4 h. The reaction mixture was diluted with MeOHand purified via preparative HPLC on a C-18 column (pH 2, 5-23%MeCN/0.1% TFA (aq) over 12 min, 60 mL/min) to afford the title compound.LCMS for C₁₉H₂₃N₇O₂S (M+H)⁺: calculated m/z=414.5; found 414.2.

Example 524.3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3-isopropyl-3-azabicyclo[3.1.1]heptan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate

Step 1. tert-butyl (3-azabicyclo[3.1.1]heptan-1-yl)carbamate

A mixture of benzyl1-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.1]heptane-3-carboxylate(236 mg, 0.681 mmol, prepared in Example 523, Step 2) and palladiumhydroxide 20% (dry basis), wet (24 mg, 0.034 mmol) in MeOH (5 mL) wasstirred under an atmosphere of H₂ (g) while stirring at ambienttemperature. The crude reaction mixture was purged with nitrogen,diluted with EtOAc (20 mL), and filtered through a pad of celite. Theinorganics were washed thoroughly with EtOAc. The volatiles were removedin-vacuo and the crude product was used in the subsequent step withoutfurther purification. LCMS for C₁₁H₂₀N₂O₂ (M+H)⁺: calculated m/z=213.3;found 213.2.

Step 2. 3-isopropyl-3-azabicyclo[3.1.1]heptan-1-amine hydrochloride

A mixture of tert-butyl (3-azabicyclo[3.1.1]heptan-1-yl)carbamate (25mg, 0.12 mmol), acetone (0.043 mL, 0.59 mmol), and sodiumtriacetoxyborohydride (42. mg, 0.20 mmol) in DCE (0.5 mL) was stirred atambient temperature overnight. 4 N HCl in 1,4-dioxane (1 mL) was addedand the resultant solution was stirred at ambient temperature for 5 h.The volatiles were removed in-vacuo and the residue was azeotropicallywashed with acetonitrile prior to placing it under high vacuum. Thecrude product was used in the subsequent reaction without furtherpurification. LCMS for C₉H₁₈N₂ (M+H)⁺: calculated m/z=155.3; found155.1.

Step 3.3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3-isopropyl-3-azabicyclo[3.1.1]heptan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate

To a solution of 3-isopropyl-3-azabicyclo[3.1.1]heptan-1-aminehydrochloride (12 mg, 0.064 mmol) and3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonylchloride (10. mg, 0.026 mmol) in DCM (0.5 mL) was added sequentiallyEt₃N (0.014 mL, 0.10 mmol), and DMAP (1.5 mg, 0.012 mmol). After 15 min.NMP (0.2 mL) was added and the resulting solution was stirred at ambienttemperature overnight. The reaction mixture was quenched by the additionof 4 N HCl (aq) (0.5 mL), diluted with MeOH, and purified viapreparative HPLC on a C-18 column (pH 2, 17-35% MeCN/0.1% TFA (aq) over12 min, 60 mL/min) to afford the title compound. LCMS for C₂₂H₂₆F₃N₇O₂S(M+H)⁺: calculated m/z=510.6; found 510.2.

Example 525.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3-cyclobutyl-3-azabicyclo[3.1.1]heptan-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate

To a solution of 3-cyclobutyl-3-azabicyclo[3.1.1]heptan-1-aminehydrochloride (13 mg, 0.064 mmol, prepared by using a procedureanalogous to that in Example 524, Steps 1-2) in DCE (1 mL) was addedsequentially 1 N Na₂CO₃ (aq) (1 mL) and3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonylchloride (8. mg, 0.03 mmol) and the resulting mixture was stirred atambient temperature overnight. The reaction mixture was quenched by theaddition of 4 N HCl (aq) (0.5 mL), diluted with MeOH, and purified viapreparative HPLC on a C-18 column (pH 2, 14-34% MeCN/0.1% TFA (aq) over5 min, 60 mL/min) to afford the title compound. LCMS for C₂₂H₂₇N₇O₂S(M+H)⁺: calculated m/z=454.6; found 454.3.

Example 526.3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1,3-dimethylpiperidin-3-yl)-4-methylbenzenesulfonamidetrifluoroacetate

Step 1. 1,3-dimethylpiperidin-3-amine hydrochloride

A mixture of tert-butyl (3-methylpiperidin-3-yl) carbamate (50. mg, 0.23mmol), paraformaldehyde (35 mg, 1.2 mmol), and sodiumtriacetoxyborohydride (84 mg, 0.40 mmol) in DCE (1.0 mL) was stirred atambient temperature overnight. 4 N HCl in 1,4-dioxane (1 mL) was addedand the resultant solution was stirred at ambient temperature for 5 h.The volatiles were removed in-vacuo and the residue was azeotropicallywashed with acetonitrile prior to placing it under high vacuum. Thecrude product was used in the subsequent reaction without furtherpurification. LCMS for C₇H₁₆N₂(M+H)⁺: calculated m/z=129.2; found 129.1.

Step 2.3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1,3-dimethylpiperidin-3-yl)-4-methylbenzenesulfonamidetrifluoroacetate

To a solution of 1,3-dimethylpiperidin-3-amine hydrochloride (10. mg,0.064 mmol) in DCE (1 mL) was added sequentially 1 N Na₂CO₃ (aq) (1 mL)and3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonylchloride (10. mg, 0.026 mmol) and the resulting mixture was stirred atambient temperature overnight. The reaction mixture was quenched by theaddition of 4 N HCl (aq) (0.5 mL), diluted with MeOH, and purified viapreparative HPLC on a C-18 column (pH 2, 8-26% MeCN/0.1% TFA (aq) over12 min, 60 mL/min) to afford the title compound. LCMS for C₂₀H₂₄F₃N₇O₂S(M+H)⁺: calculated m/z=484.5; found 484.2.

Example 527.3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1-isopropyl-3-methylpiperidin-3-yl)-4-methylbenzenesulfonamidetrifluoroacetate

A procedure analogous to that outlined in Example 526 was used with theexception that 1-isopropyl-3-methylpiperidin-3-amine hydrochloride (12mg, 0.064 mmol) was used as the amine. LCMS for C₂₂H₂₈F₃N₇O₂S (M+H)⁺:calculated m/z=512.6; found 512.3.

Example 528.3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1,4-dimethylpiperidin-4-yl)-4-methylbenzenesulfonamidetrifluoroacetate

To a vial containing3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonylchloride (10 mg, 0.026 mmol) and DMAP (2.0 mg, 0.016 mmol) was added asolution of 1,4-dimethylpiperidin-4-amine hydrochloride (9.2 mg, 0.056mmol, prepared in a manner similar to that outlined in Example 526,step 1) and Et₃N (0.014 mL, 0.10 mmol) in DCM (0.6 mL) and NMP (0.4 mL)and the resulting mixture was stirred at ambient temperature overnight.A second aliquot of sulfonyl chloride was added and stirring wascontinued overnight. The reaction was diluted with methanol (4 mL),acidified by the addition of 4 N HCl (aq) (0.5 mL), syringe filtered,and purified via preparative HPLC on a C-18 column (pH 2, 16-34%MeCN/0.1% TFA (aq) over 12 min, 60 mL/min) to afford the title compound.LCMS for C₂₀H₂₄F₃N₇O₂S (M+H)⁺: calculated m/z=484.5; found 484.2.

Example 529.3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(3-cyanocyclobutyl)-4-methylpiperidin-4-yl)-4-methylbenzenesulfonamidetrifluoroacetate

A procedure analogous to that outlined in Example 528 was used with theexception that3-(4-amino-4-methylpiperidin-1-yl)cyclobutane-1-carbonitrilehydrochloride (13 mg, 0.056 mmol) was used as the amine. LCMS forC₂₄H₂₇F₃N₅O₂S (M+H)⁺: calculated m/z=549.6; found 549.1.

Example 530.3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-(4-methyl-1-(tetrahydrofuran-3-yl)piperidin-4-yl)benzenesulfonamidetrifluoroacetate

A procedure analogous to that outlined in Example 528 was used with theexception that 4-methyl-1-(tetrahydrofuran-3-yl)piperidin-4-aminehydrochloride (12 mg, 0.056 mmol) was used as the amine. LCMS forC₂₃H₂₈F₃N₇O₃S (M+H)⁺: calculated m/z=540.6; found 540.1.

Example 531.3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-(3-methylazetidin-3-yl)benzenesulfonamidetrifluoroacetate

Step 1. benzyl3-((tert-butoxycarbonyl)amino)-3-methylazetidine-1-carboxylate

To a 0° C. solution of tert-butyl (3-methylazetidin-3-yl) carbamate (200mg, 1.074 mmol) and Et₃N (0.299 mL, 2.15 mmol) in DCM (6 mL) was addedbenzyl chloroformate (0.18 mL, 1.3 mmol) drop-wise. The solution wasallowed to gradually warm to ambient temperature while stirring for 3 h.The crude reaction mixture was purified by CombiFlash chromatography (25g silica gel column, eluting with 0-15% methanol/dichloromethane) toafford the desired product (183 mg, 53%). LCMS for C₁₇H₂₄N₂O₄ (M+Na)⁺:calculated m/z=343.4; found 343.1.

Step 2. benzyl 3-amino-3-methylazetidine-1-carboxylate trifluoroacetate

Benzyl 3-((tert-butoxycarbonyl)amino)-3-methylazetidine-1-carboxylate(56 mg, 0.18 mmol) was dissolved in DCM (1 mL) and to this was added TFA(1 mL) and the resulting solution was stirred at ambient temperature for4 h. The volatiles were removed in-vacuo and the crude product wasazeotropically washed with acetonitrile and placed under high vacuumprior to use in the subsequent reaction. LCMS for C₁₂H₁₆N₂O₂ (M+H)⁺:calculated m/z=221.3; found 221.1.

Step 3.3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-(3-methylazetidin-3-yl)benzenesulfonamidetrifluoroacetate

A procedure analogous to that outlined in Example 523 steps 4-5 was usedwith the exception that benzyl 3-amino-3-methylazetidine-1-carboxylatetrifluoroacetate (33 mg, 0.130 mmol) was used as the amine. LCMS forC₁₇H₁₈F₃N₇O₂S (M+H)⁺: calculated m/z=442.4; found 442.2.

Example 532.3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1,3-dimethylazetidin-3-yl)-4-methylbenzenesulfonamide

A procedure analogous to that outlined in Example 523 step 6 was usedwith the exception that 3-(4-amino-2-(trifluoromethyl)imidazo[2,l-f][1,2,4]triazin-7-yl)-4-methyl-N-(3-methylazetidin-3-yl)benzenesulfonamide(18 mg, 0.041 mmol) was used as the amine. The reaction mixture wasdiluted with MeOH and purified via preparative HPLC on a C-18 column (pH10, 20-38% MeCN/NH₄OH (aq) over 12 min, 60 mL/min) to afford the titlecompound. LCMS for C₁₈H₂₀F₃N₇O₂S (M+H)⁺: calculated m/z=456.5; found456.1.

Example 533.3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1,3-dimethylpyrrolidin-3-yl)-4-methylbenzenesulfonamidetrifluoroacetate

A procedure analogous to that outlined in Example 526 steps 1-2 was usedwith the exception that tert-butyl (3-methylpyrrolidin-3-yl)carbamatewas used as the starting amine. LCMS for C₁₉H₂₂F₃N₇O₂S (M+H)⁺:calculated m/z=470.5; found 470.2.

Example 534.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanocuban-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate

Step 1. Methyl-4-aminocubane-1-carboxylate hydrochloride

To a solution ofmethyl-4-((tert-butoxycarbonyl)amino)cubane-1-carboxylate (150 mg, 0.541mmol) in THF (2.0 mL) was added 4 N HCl in 1,4-dioxane (2.0 mL, 8.0mmol) and the solution was stirred at ambient temperature overnight. Thevolatiles were removed in-vacuo and the residue was placed under highvacuum prior to using in the subsequent reaction. LCMS for C₁₀H₁₁NO₂(M+H)⁺: calculated m/z=178.2; found 178.1.

Step 2. methyl4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonamido)cubane-1-carboxylate

To a solution of methyl-4-aminocubane-1-carboxylate (96 mg, 0.54 mmol),Et₃N (0.30 mL, 2.2 mmol), and DMAP (6.6 mg, 0.054 mmol) in DCM (0.5 mL)was added3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonylchloride (175 mg, 0.541 mmol) and the resulting solution was stirred atambient temperature for 6 h. The crude reaction mixture was purified byCombiFlash chromatography (25 g silica gel column, eluting with 0-15%methanol/dichloromethane) to afford the desired product (93 mg, 38%).LCMS for C₂₂H₂₀N₆O₄S (M+H)⁺: calculated m/z=465.5; found 465.2.

Step 3.4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonamido)cubane-1-carboxamide

A solution of methyl4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonamido)cubane-1-carboxylate(20 mg, 0.043 mmol) in ammonia in methanol 7 N (1.0 mL, 7.0 mmol) wasstirred at ambient temperature overnight. The volatiles were removedin-vacuo and the crude product was used in the subsequent reactionwithout further purification. LCMS for C₂₁H₁₉N₇O₃S (M+H)⁺: calculatedm/z=450.5; found 450.2.

Step 4.3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanocuban-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate

4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonamido)cubane-1-carboxamideformed above was dissolved in anhydrous DCM (1.0 mL) and to this wasadded sequentially Et₃N (0.024 mL, 0.17 mmol) and trifluoroaceticanhydride (7.0 μL, 0.050 mmol) and the resulting solution was stirred atambient temperature. After 2 h, a second aliquot of Et₃N and TFAA wereadded and stirring was continued for an additional 2 h. The reactionmixture was diluted with MeOH and purified via preparative HPLC on aC-18 column (pH 2, eluting with MeCN/0.1% TFA (aq)). LCMS forC₂₁H₁₇N₇O₂S (M+H)⁺: calculated m/z=432.5; found 432.1.

Example 535.3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-(2-hydroxypropan-2-yl)cuban-1-yl)-4-methylbenzenesulfonamidetrifluoroacetate

To a solution of methyl4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonamido)cubane-1-carboxylate(20 mg, 0.043 mmol) in anhydrous THF (1.0 mL) was added 3 Mmethylmagnesium bromide in ether (0.072 mL, 0.22 mmol) and the resultingsolution was stirred at ambient temperature overnight. The reactionmixture was diluted with MeOH and purified via preparative HPLC on aC-18 column (pH 2, 16-34% MeCN/0.1% TFA (aq) over 12 min, 60 mL/min)afforded the title compound. LCMS for C₂₃H₂₄N₆O₃S (M+H)⁺: calculatedm/z=465.5; found 465.3.

Example 536.3-(2-Methyl-5-(methylsulfonyl)phenyl)-6-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-a]pyrazin-8-aminetrifluoroacetate

Step 1.6-(3,6-dihydro-2H-pyran-4-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-amine

A mixture of2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(28 mg, 0.13 mmol),6-bromo-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-amine(25 mg, 0.065 mmol), Pd(Ph₃P)₄ (7.5 mg, 0.006 mmol), and K₂CO₃ (27 mg,0.20 mmol) in 1,4-dioxane (1.0 mL) was de-gassed and purged withnitrogen several times prior to heating at 110° C. in a sealed vialovernight. The crude reaction mixture was diluted with EtOAc (20 mL) andfiltered through a pad of celite. The inorganics were washed thoroughlywith EtOAc. The volatiles were removed in-vacuo and the crude productwas purified by CombiFlash chromatography (12 g silica gel column,eluting with 0-20% methanol/dichloromethane) to afford the desiredproduct (11 mg, 44%). LCMS for C₁₉H₂₀N₄O₃S (M+H)⁺: calculated m/z=385.5;found 385.2.

Step 2.3-(2-Methyl-5-(methylsulfonyl)phenyl)-6-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-a]pyrazin-8-aminetrifluoroacetate

A mixture of6-(3,6-dihydro-2H-pyran-4-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-amine(5.5 mg, 0.014 mmol) and palladium hydroxide (2.0 mg, 2.9 μmol) in MeOH(2 mL) and THF (1 mL) was stirred under an atmosphere of H₂ (g) via aballoon. The crude reaction mixture was purged with nitrogen, dilutedwith EtOAc (10 mL), and filtered through a pad of celite. The inorganicswere washed thoroughly with EtOAc. The volatiles were removed in-vacuoand the crude product was diluted with MeOH and purified via preparativeHPLC on a C-18 column (pH 2, 13-33% MeCN/0.1% TFA (aq) over 5 min, 60mL/min) to afford the title compound. LCMS for C₁₉H₂₂N₄O₃S (M+H)⁺:calculated m/z=387.5; found 387.1.

Example 537.1-(4-(8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-6-yl)piperidin-1-yl)ethan-1-onetrifluoroacetate

Step 1.3-(2-methyl-5-(methylsulfonyl)phenyl)-6-(piperidin-4-yl)imidazo[1,2-a]pyrazin-8-amine

A procedure analogous to that outlined in Example 536, steps 1-2 wasused with the exception that benzyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(90 mg, 0.26 mmol) was used as the starting boronic ester. LCMS forC₁₉H₂₃N₅O₂S (M+H)⁺: calculated m/z=386.5; found 386.2.

Step 2.1-(4-(8-amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-6-yl)piperidin-1-yl)ethan-1-onetrifluoroacetate

To a 0° C. solution of3-(2-methyl-5-(methylsulfonyl)phenyl)-6-(piperidin-4-yl)imidazo[1,2-a]pyrazin-8-amine(15 mg, 0.039 mmol) in DCM (1 mL) was added a solution of acetylchloride (3.0 μL, 0.043 mmol) in DCM (0.5 mL) and the resulting solutionwas allowed to gradually warm to ambient temperature overnight. Thereaction mixture was diluted with MeOH and purified via preparative HPLCon a C-18 column (pH 2, 11-31% MeCN/0.1% TFA (aq) over 5 min, 60 mL/min)to afford the title compound. LCMS for C₂₁H₂₅N₅O₃S (M+H)⁺: calculatedm/z=428.5; found 428.2.

Example 538. Methyl3-(8-amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-6-yl)pyrrolidine-1-carboxylatetrifluoroacetate

A procedure analogous to that outlined in Example 537 steps 1-2 was usedwith the exception that tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(77 mg, 0.26 mmol) was used as the starting boronic ester in step 1 andmethyl chloroformate was used as the acylating reagent in step 2. LCMSfor C₂₀H₂₃N₅O₄S (M+H)⁺: calculated m/z=430.5; found 430.1.

Example 539.5-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonamido)-N-(2,2,2-trifluoroethyl)picolinamidetrifluoroacetate

To a solution of 2,2,2-trifluoroethylamine (0.015 mL, 0.19 mmol) inanhydrous DCM (0.5 mL) was added 2.0 M trimethylaluminum in toluene(0.10 mL, 0.20 mmol) and the resulting solution was stirred at ambienttemperature for 30 min. This solution was added via syringe to a cloudysolution of methyl5-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonamido)picolinate(14 mg, 0.032 mmol) in anhydrous DCM (0.5 mL). The resulting mixture wasstirred overnight. The crude reaction mixture was diluted with DCM (10mL) and quenched by the careful addition of MeOH followed by saturatedNH₄Cl (aq) and the resulting slurry was stirred for 10 min. The crudereaction mixture was filtered through a pad of celite and the inorganicswere washed thoroughly with DCM. The volatiles were removed in-vacuo andthe crude product was diluted with MeOH and purified via preparativeHPLC on a C-18 column (pH 2, 23-41% MeCN/0.1% TFA (aq) over 12 min, 60mL/min) to afford the title compound. LCMS for C₂₀H₁₇F₃N₈O₃S (M+H)⁺:calculated m/z=507.5; found 507.2.

Example A. THP-1 RPS6 ELISA Assay

To measure the Phosphorylated Ribosomal Protein S6 (RPS6) in celllysates, THP-1 cells (Human Acute Monocytic Leukemia) are purchased fromATCC (Manassas, Va.) and maintained in RPMI with 10% FBS (Gibco/LifeTechnologies, Carlsbad, Calif.). For the assay, THP-1 cells are serumstarved overnight in RPMI, then plated in RPMI (2×10⁵ cells/well in 90μL) into 96-well flat-bottom tissue culture treated plates (Corning,Corning, N.Y.), in the presence or absence of a concentration range oftest compounds. Covered plates are incubated for 2 hours at 37° C., 5%CO₂ then treated with or without 10 nM MCP-1(MYBioSource, San Diego,Calif.) for 15 minutes at 37° C., 5% CO₂. Plates are centrifuged at 1600RPM and supernatants are removed. Cells are lysed in Lysis Buffer (CellSignaling, Danvers, Mass.) with Protease Inhibitor (Calbiochem/EMD,Germany), PMSF (Sigma, St Louis Mo.), HALTS (Thermo Fisher, Rockford,Ill.) for 30 min on wet ice. Cell lysates are frozen at −80° C. beforetesting. The lysates are tested in the Human/Mouse/Rat Phospho-RPS6ELISA (R&D Systems, Inc. Minn, Minn.). The plate is measured using amicroplate reader (SpectraMax M5-Molecular Devices, LLC Sunnyvale,Calif.) set to 450 nm with a wavelength correction of 540. IC₅₀determination is performed by fitting the curve of inhibitor percentinhibition versus the log of the inhibitor concentration using theGraphPad Prism 5.0 software.

Example B. PI3K-γ Scintillation Proximity Assay

Materials

[γ-³³P]ATP (10 mCi/mL) and Wheat Germ Agglutinin (WGA) YSi SPAScintillation Beads was purchased from Perkin-Elmer (Waltham, Mass.).Lipid kinase substrate, D-myo-Phosphatidylinositol 4,5-bisphosphate(PtdIns(4,5)P2)D (+)-sn-1,2-di-O-octanoylglyceryl, 3-O-phospho linked(PIP2), CAS 204858-53-7, was purchased from Echelon Biosciences (SaltLake City, Utah). PI3Kγ (p110γ) Recombinant Human Protein was purchasedfrom Life technology (Grand Island, N.Y.). ATP, MgCl₂, DTT, EDTA, MOPSand CHAPS were purchased from Sigma-Aldrich (St. Louis, Mo.).

The kinase reaction was conducted in polystyrene 384-well GreinerBio-one white plate from Thermo Fisher Scientific in a final volume of25 μL. Inhibitors were first diluted serially in DMSO and added to theplate wells before the addition of other reaction components. The finalconcentration of DMSO in the assay was 2%. The PI3Kγ assay was carriedout at room temperature in 20 mM MOPS, pH 6.7, 10 mM MgCl₂, 5 mM DTT andCHAPS 0.03%. Reactions were initiated by the addition of ATP, the finalreaction mixture consisted of 20 μM PIP2, 2 μM ATP, 0.5 μCi [γ-³³P] ATP,13 nM PI3Kγ. Reactions were incubated for 120 min and terminated by theaddition of 40 μL SPA beads suspended in quench buffer: 163 mM potassiumphosphate pH 7.8, 20% glycerol, 25 mM EDTA. The final concentration ofSPA beads is 1.0 mg/mL. After the plate sealing, plates were shakenovernight at room temperature and centrifuged at 1500 rpm for 10 min,the radioactivity of the product was determined by scintillationcounting on Topcount (Perkin-Elmer). IC₅₀ determination was performed byfitting the curve of percent of the solvent control activity versus thelog of the inhibitor concentration using the GraphPad Prism 6.0software. Data for the Examples, obtained using the methods described inExample B, are provided in Table 22.

Example C. PI3Kδ Scintillation Proximity Assay

Materials

[γ-³³P]ATP (10 mCi/mL) and Wheat Germ Agglutinin (WGA) YSi SPAScintillation Beads was purchased from Perkin-Elmer (Waltham, Mass.).Lipid kinase substrate, D-myo-Phosphatidylinositol 4,5-bisphosphate(PtdIns(4,5)P2)D (+)-sn-1,2-di-O-octanoylglyceryl, 3-O-phospho linked(PIP2), CAS 204858-53-7, was purchased from Echelon Biosciences (SaltLake City, Utah). PI3Kδ (p110δ/p85α) Recombinant Human Protein waspurchased from Eurofins (St Charles, Mo.). ATP, MgCl₂, DTT, EDTA, MOPSand CHAPS were purchased from Sigma-Aldrich (St. Louis, Mo.).

The kinase reaction was conducted in polystyrene 384-well GreinerBio-one white plate from Thermo Fisher Scientific in a final volume of25 μL. Inhibitors were first diluted serially in DMSO and added to theplate wells before the addition of other reaction components. The finalconcentration of DMSO in the assay was 2%. The PI3Kδ assay was carriedout at room temperature in 20 mM MOPS, pH 6.7, 10 mM MgCl₂, 5 mM DTT andCHAPS 0.03%. Reactions were initiated by the addition of ATP, the finalreaction mixture consisted of 20 μM PIP2, 2 μM ATP, 0.5 μCi [γ-³³P] ATP,3.4 nM PI3Kδ. Reactions were incubated for 120 min and terminated by theaddition of 40 μL SPA beads suspended in quench buffer: 163 mM potassiumphosphate pH 7.8, 20% glycerol, 25 mM EDTA. The final concentration ofSPA beads is 1.0 mg/mL. After the plate sealing, plates were shakenovernight at room temperature and centrifuged at 1500 rpm for 10 min,the radioactivity of the product was determined by scintillationcounting on Topcount (Perkin-Elmer). IC₅₀ determination was performed byfitting the curve of percent of the solvent control activity versus thelog of the inhibitor concentration using the GraphPad Prism 6.0software.

Data for the Examples, obtained using the methods described in ExamplesA, B and C, are provided in Table 22.

TABLE 22 PI3Kγ PI3Kδ PI3Kγ_THP1_RPS6_ELISA Ex. No. IC₅₀ (nM) IC₅₀ (nM)IC₅₀ (nM) 1 ++ +++ #### 2 ++ +++ #### 3 ++ ++++ − 4 + ++ # 5 + ++ ## 6+++ ++++ − 7 ++ +++ − 8 + ++ #### 9 + +++ #### 10 + ++ #### 11 + +++ #12 + ++ ## 13 + ++ ## 14 + + #### 15 + +++ #### 16 + + # 17 + ++ ## 18 +++ # 19 + ++ # 20 + + # 21 + + # 22 + + # 23 + + # 24 + + ## 25 + ++ ##26 + + ## 27 + ++ # 28 + ++ ## 29 + ++ #### 30 + + # 31 + + #### 32 + +# 33 + ++ ### 34 + ++ ## 35 + ++ # 36 + + # 37 + + ## 38 + + # 39 + ++## 40 + ++ − 41 + ++ #### 42 + +++ ### 43 ++ + − 44 +++ ++++ − 45 + +++− 46 + ++ − 47 + +++ #### 48 + +++ #### 49 + +++ #### 50 + +++ #### 51 ++++ #### 52 + ++ ### 53 + +++ #### 54 + ++ #### 55 + ++++ #### 56 + +++#### 57 + +++ #### 58 ++ +++ #### 59 + +++ #### 60 + ++ ## 61 + +++ ###62 + ++ ## 63 + ++ ## 64 + ++++ #### 65 + ++++ #### 66 ++ ++++ − 67 ++++++ 68 + +++ ### 69 + +++ ## 70 + +++ #### 71 + ++++ ## 72 + ++++ ####73 + +++ #### 74 + +++ #### 75 + + ## 76 + ++ ## 77 + ++ ## 78 + ++ ###79 + + ## 80 + ++ ## 81 + + # 82 + + # 83 ++ + #### 84 + +++ #### 85 ++++ ## 86 + +++ #### 87 + ++ ## 88 + ++ # 89 + ++ # 90 + ++ # 91 + ++ ##92 + ++ # 93 + ++ ## 94 + ++ ### 95 + ++ ## 96 + ++ #### 97 + ++ ## 98 ++++ ## 99 + +++ #### 100 + +++ ### 101 + +++ #### 102 + ++ ## 103 + +++#### 104 + +++ ### 105 + +++ − 106 + +++ #### 107 + ++ ### 108 + ++ ##109 + +++ #### 110 + ++ #### 111 + ++ ## 112 + ++ ## 113 + +++ ## 114 +++ ## 115 + +++ ## 116 + +++ ## 117 + +++ ## 118 + ++ #### 119 ++ ++++ −120 + ++ − 121 ++ ++++ #### 122 + +++ ## 123 + +++ ### 124 + ++ ## 125 ++++ #### 126 + +++ ## 127 + +++ ## 128 + ++ ## 129 + ++ # 130 + +++ ###131 ++ +++ #### 132 + ++ ## 133 + +++ #### 134 + +++ ## 135 + ++ ####136 ++ ++++ #### 137 + +++ #### 138 + +++ #### 139 + +++ #### 140 + +++## 141 + ++ ## 142 + +++ ## 143 + ++ #### 144 + ++ ### 145 + ++ ## 146 +++ − 147 + ++ ## 148 ++ +++ − 149 + ++ − 150 + +++ − 151 + ++ − 152 ++++ − 153 + +++ − 154 + ++++ − 155 + ++ ## 156 + +++ ### 157 + +++ ###158 + +++ − 159 ++ ++++ − 160 ++ +++ − 161 + ++ − 162 + +++ − 163 + +++− 164 + +++ − 165 + ++ ### 166 + ++ ## 167 ++ ++++ − 168 + +++ − 169 ++++++ − 170 + +++ − 171 ++ +++ − 172 ++ +++ − 173 ++ ++++ − 174 ++ ++++ −175 + ++ ## 176 ++ ++++ − 177 + +++ − 178 + +++ − 179 + +++ − 180 + ++## 181 + + ## 182 + +++ ### 183 + ++ # 184 + + # 185 + ++ ## 186 + ++ ##187 + ++ ## 188 + + ## 189 + +++ ### 190 + +++ #### 191 + +++ − 192 + ++### 193 + +++ − 194 + +++ ## 195 + ++ − 196 + +++ − 197 + +++ ### 198 +++++ − 199 + +++ ### 200 + +++ − 201 + +++ − 202 ++ +++ − 203 + ++ ###204 ++ +++ − 205 + +++ #### 206 + +++ #### 207 + ++ − 208 + +++ ###209 + +++ − 210 + ++ ## 211 + +++ ### 212 + +++ ### 213 + +++ − 214 + −− 215 + − − 216 + − − 217 + − − 218 + − − 219 ++ − − 220 + − − 221 + − −222 + − − 223 + − − 224 + − − 225 + − − 226 + − − 227 + − − 228 + − −229 + − − 230 + − − 231 + − − 232 + − − 233 + − − 234 ++ − − 235 + − −236 + − − 237 + − − 238 ++ − − 239 +++ − − 240 + − − 241 + − − 242 + − −243 + − − 244 + − − 245 + − − 246 + − − 247 + − − 248 + − − 249 + ++ ##250 + ++ ## 251 + ++ # 252 + ++ ## 253 + ++ # 254 + ++ # 255 + ++ #256 + ++ ## 257 + +++ #### 258 + ++ ### 259 + ++ # 260 + +++ − 261 + +++# 262 + + ## 263 + ++ ## 264 + ++ ## 265 + + # 266 + ++ ## 267 + ++ ##268 + ++ ## 269 + ++ ## 270 + ++ # 271 + ++ # 272 + ++ ## 273 + +++ ##274 + ++ # 275 + ++ ## 276 + ++ # 277 + ++ # 278 + ++ # 279 + + # 280 +++ ## 281 + ++ ## 282 + ++ # 283 + ++ ## 284 + ++ ## 285 + ++ ## 286 +++ # 287 + ++ # 288 + ++ ## 289 + ++ ## 290 + +++ #### 291 + ++ ###292 + +++ #### 293 + ++ ## 294 + +++ #### 295 + +++ #### 296 + +++ ##297 + +++ − 298 + +++ − 299 + ++ ## 300 + +++ − 301 + +++ ## 302 + +++ −303 + +++ − 304 + +++ − 305 + ++ #### 306 + + # 307 + + ## 308 + + #309 + +++ ## 310 + ++ # 311 + ++ # 312 + ++ ## 313 + ++ − 314 + ++ ##315 + + # 316 + ++ # 317 + ++ # 318 + ++ # 319 + ++ # 320 + ++ ##321 + + # 322 + ++ # 323 + ++ # 324 + ++ # 325 + + ## 326 + ++ # 327 +++ ## 328 + ++ # 329 + ++ ## 330 + + # 331 + ++ ## 332 + ++ # 333 + ++ #334 + ++ # 335 + ++ ## 336 + ++ ## 337 + ++ ## 338 + ++ ## 339 + ++ ##340 + ++ ## 341 + ++ ## 342 + ++ ## 343 + + # 344 + + ## 345 + ++ ####346 + ++ ## 347 + ++ # 348 + + ## 349 + +++ − 350 ++ +++ − 351 + +++ −352 + +++ − 353 + +++ #### 354 + +++ #### 355 + ++ ## 356 + ++ # 357 + −− 358 + − − 359 + ++ #### 360 ++ ++ #### 361 ++ ++ − 362 + ++ # 363 ++++ ## 364 + ++ # 365 + ++ ## 366 + ++ − 367 + ++ #### 368 + ++ − 369 +++ − 370 + ++ # 371 + ++ ## 372 + +++ − 373 +++ +++ − 374 + +++ ###375 + ++ # 376 + ++ #### 377 + + # 378 + ++ # 379 + ++ # 380 + +++ ####381 + ++ ## 382 ++ +++ − 383 + + # 384 + + ### 385 + + ## 386 + ++ #387 + ++ # 388 + ++ #### 389 + + # 390 + ++ ## 391 + ++ # 392 + + ##393 + +++ ## 394 + ++ ## 395 + ++ ## 396 + ++ ### 397 + ++ # 398 + ++### 399 + + #### 400 + + # 401 + ++++ − 402 + ++ ## 403 + ++ # 404 + + #405 + ++ # 406 + + # 407 +++ ++++ − 408 + ++ #### 409 + ++ ## 410 + + #411 + ++ ## 412 + ++ # 413 + ++ # 414 + + ## 415 + ++ # 416 + ++ # 417 +++ ### 418 + ++ #### 419 + = #### 420 + ++ ## 421 + + # 422 + + #423 + + # 424 + ++ ## 425 + ++ # 426 + ++ ## 427 + ++ ## 428 + ++ ##429 + ++ ## 430 + ++ ## 431 + ++ ## 432 + ++ ## 433 + ++ ## 434 + ++ ##435 + ++ ### 436 + ++ ## 437 + ++ ## 438 + ++ # 439 + +++ ### 440 + ++## 441 + ++ ## 442 + +++ ## 443 + + ## 444 + + ## 445 + ++ ## 446 + ++## 447 + +++ ### 448 + +++ ## 449 + ++ #### 450 + ++ ### 451 + ++ ###452 ++++ ++ − 453 ++ ++ − 454 ++ +++ − 455 +++ +++ − 456 ++ ++ − 457 ++++ − 458 +++ ++++ − 459 ++ ++++ − 460 +++ ++++ − 461 ++ +++ − 462 + +++− 463 + ++ ## 464 + + # 465 + +++ ## 466 + + # 467 + ++ # 468 + ++ ##469 + ++ ## 470 + +++ − 471 ++ +++ #### 472 + ++ ## 473 + +++ − 474 + ++## 475 + ++ ### 476 + ++ ## 477 + ++ ## 478 ++ +++ − 479 + ++ − 480 + ++− 481 + ++ ## 482 + +++ #### 483 + + #### 484 + ++ ## 485 + ++ ## 486 +++ ## 487 + ++ − 488 + ++ ## 489 + ++ ## 490 + ++ # 491 + ++ ## 492 ++++ ### 493 ++ ++++ #### 494 + +++ #### 495 + +++ #### 496 + +++ ### 497++ +++ − 498 + +++ − 499 ++ +++ − 500 + +++ ## 501 + +++ − 502 + + ##503 + + ## 504 + + # 505 + + ## 506 + + # 507 + ++ ### 508 + ++ ###509 + +++ #### 510 + ++ #### 511 +++ ++++ − 512 + ++++ − 513 + ++ ## 514++ +++ − 515 ++ ++++ − 516 + + # 517 + +++ − 518 ++ +++ ## 519 ++ + ####520 + − − 521 + − − 522 + − − 523 + − − 524 + − − 525 ++ − − 526 + − −527 + − − 528 + − − 529 ++ − − 530 ++ − − 531 + − − 532 + − − 533 + − −534 + − − 535 + − − 536 + − − 537 + − − 538 ++ − − 539 + − − + refers toIC₅₀ of ≤100 nM; ++ refers to IC₅₀ of ≤500 nM; +++ refers to an IC₅₀ of<2000 nM; ++++ refers to an IC₅₀ of ≥2000 nM. # refers to IC₅₀ of ≤100nM; ## refers to IC₅₀ of ≤500 nM; ### refers to IC₅₀ of <1000 nM; ####refers to an IC₅₀ of ≥1000 nM.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

1. A compound of Formula (I):

or a pharmaceutically acceptable salt or a tautomer thereof; wherein: X¹is N; X² is N; X³ is CR³; X⁴ is CR⁴; X⁵ is CR⁵; X⁶ is CR⁶; R⁷ is H; R³,R⁵, and R⁶ are each H; R⁴ is CD₃, or methyl; R⁸ is H, CF₃, or methyl; R⁹is H; R¹⁰ is C₁₋₆alkyl, optionally substituted with 1, or 2independently selected R^(b) substituents; L is

and R^(b) is OH. 2-48. (canceled)
 49. A compound, selected from:3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-methylbenzenesulfonamide;3-(4-amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamide;and3-(4-Amino-2-methylimidazo[2,1-f][1,2,4]triazin-7-yl)-5-fluoro-N-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamide;or a pharmaceutically acceptable salt or a tautomer thereof. 50-53.(canceled)
 54. A pharmaceutical composition comprising a compound ofclaim 49, or a pharmaceutically acceptable salt or a tautomer thereof,and a pharmaceutically acceptable excipient or carrier. 55-75.(canceled)
 76. The compound of claim 49, which is3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-methylbenzenesulfonamideor a pharmaceutically acceptable salt or a tautomer thereof.
 77. Apharmaceutical composition comprising a compound of claim 76, or apharmaceutically acceptable salt or a tautomer thereof.
 78. The compoundof claim 49, which is3-(4-amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamideor a pharmaceutically acceptable salt or a tautomer thereof.
 79. Thecompound of claim 78, wherein one or more hydrogen atoms are replaced byone or more deuterium atoms.
 80. A pharmaceutical composition comprisinga compound of claim 79, or a pharmaceutically acceptable salt or atautomer thereof.
 81. A pharmaceutical composition comprising a compoundof claim 78, or a pharmaceutically acceptable salt or a tautomerthereof.
 82. The compound of claim 49, which is3-(4-Amino-2-methylimidazo[2,1-f][1,2,4]triazin-7-yl)-5-fluoro-N-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamideor a pharmaceutically acceptable salt or a tautomer thereof.
 83. Apharmaceutical composition comprising a compound of claim 82, or apharmaceutically acceptable salt or a tautomer thereof.
 84. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt or a tautomer thereof, and apharmaceutically acceptable excipient or carrier.